Antiviral compounds

ABSTRACT

The invention is related to anti-viral compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

PRIORITY OF INVENTION

This application claims priority to U.S. Provisional Application Nos.61/414,818, filed 17 Nov. 2010 and 61/504,924 filed 6 Jul. 2011. Theentire content of each of these applications is hereby incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Hepatitis C is recognized as a chronic viral disease of the liver whichis characterized by liver disease. Although drugs targeting the liverare in wide use and have shown effectiveness, toxicity and other sideeffects have limited their usefulness. Inhibitors of hepatitis C virus(HCV) are useful to limit the establishment and progression of infectionby HCV as well as in diagnostic assays for HCV.

There is a need for new HCV therapeutic agents. In particular, there isa need for HCV therapeutic agents that have broad activity against HCVgenotypes (e.g. genotypes 1a, 1b, 2a, 3a, 4a). There is also aparticular need for agents that are less susceptible to viralresistance. Resistance mutations to inhibitors have been described forHCV NS5A for genotypes 1a and 1b in Antimicrobial Agents andChemotherapy, September 2010, Volume 54, p. 3641-3650.

SUMMARY OF THE INVENTION

In one embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

P^(1a) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected fromhydrogen and alkyl; and where in arylalkyl the alkyl can be substitutedwith up to three aryl groups, and the alkyl part of the arylalkyl isfurther optionally substituted with one or two additional groupsindependently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy,haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group,arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R¹¹;

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

pq is independently 0, 1, 2, 3, or 4;

-   -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl.(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d), (NR^(c)R^(d))alkenyl,(NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl; R^(c) and R^(d) areindependently selected from hydrogen, alkenyloxycarbonyl with one or twogroups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,cycloalkyl, and cycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; and

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁴ is a six membered aromatic or heteroaromatic or five memberedheteroraromatic ring;

X⁵ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁵ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Z⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Z⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —CH₂—O—CH₂—, —S—, —S(O)₂—, —C(O)—,—CF₂—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—; and

Z⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰,P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) and P^(1b) isselected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ andP³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        NR^(hh)R^(h))alkyl, (NR^(h)R^(h))carbonyl, wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

Y¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

X¹⁴ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

each Y¹⁶ is a bicyclic aromatic ring system comprising eight to 12 atomsoptionally including one or more heteroatoms selected from O, S, and N,which bicyclic ring system is optionally with one or more groupsindependently selected from halo, haloalkyl, alkyl and oxo.

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰,P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) and P^(1b) isselected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ andP³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

Y¹⁸ is selected from A⁰, A¹, A², A³, A⁷, A¹⁵, A¹⁶, and A²⁰;

each A⁰ is independently:

wherein:

-   -   each R^(A3) is independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl,        halo, haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b)        (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl; R^(a) and R^(b)        are each independently selected from the group consisting of        hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,        arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        and heterocyclylalkyl; and each    -   bb is independently 0, 1, 2, 3, or 4; or    -   each A⁰ is independently a six-membered heteroaromatic ring        containing one, two, or three nitrogen atoms, which ring is        optionally substituted with 1, 2, 3, or 4 R^(A3) groups;

each A¹ is independently:

wherein:

-   -   each R^(A1) is independently selected from cyano, nitro, SOR⁴,        SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,        cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl,        (heterocycle)alkyl, wherein each alkyl, heterocycle and        cycloalkyl is optionally substituted with one or more halo; and    -   each R⁴ is independently selected from H, alkyl, haloalkyl,        aryl, and arylalkyl;    -   each cc is independently 1, 2, 3, or 4;

each A² is independently:

wherein:

-   -   each R^(A1) is independently selected from cyano, nitro, SOR⁴,        SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,        cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl,        (heterocycle)alkyl, wherein each alkyl, heterocycle and        cycloalkyl is optionally substituted with one or more halo;

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl;

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bband cc is 1, 2, 3, or 4;

each A³ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is substituted with one ormore R^(A1) groups, and which ring is optionally substituted with one ormore R^(A3) groups;

each A⁷ is independently:

wherein:

-   -   each H⁷ is independently a five-membered heteroaromatic ring,        which H⁷ is optionally substituted with one or more groups        independently selected from R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each        R is independently selected from H or alkyl;

each A¹⁵ is independently:

wherein:

-   -   each H¹⁴ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic carbocycle which is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A¹⁶ is independently:

wherein:

-   -   each H¹⁵ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic heterocycle that comprises at        least one heteroatom in the ring system, which ring system is        optionally substituted with one or more groups independently        selected from R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A²⁰ is independently a 5 or 6 membered heteroaryl ring that isoptionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3);

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P²⁰ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; and

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

X¹⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰, E¹, or E², Or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

P^(1a) and P^(1b) are each independently selected from P⁰, P¹, P³, P⁵,P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹, and P³⁰;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(h)R^(h))alkyl, (NR^(h)R^(h))carbonyl, wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(—O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(b), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X²⁰ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

Y²¹ is a bicyclic aromatic ring system comprising eight to 12 atomsoptionally including one or more heteroatoms selected from O, S, and N,which bicyclic ring system is optionally with one or more groupsindependently selected from halo, haloalkyl, alkyl and oxo;

Y²² is selected from A⁰, A¹, A², A³, A⁷, A¹⁵, A¹⁶, and A²⁰;

each A⁰ is independently:

wherein:

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl; and each bb is independently 0, 1,2, 3, or 4; or

each A⁰ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is optionally substitutedwith 1, 2, 3, or 4 R^(A3) groups;

each A¹ is independently:

wherein:

each R^(A1) is independently selected from cyano, nitro, SOR⁴, SO₂R⁴,-alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl,(halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl,wherein each alkyl, heterocycle and cycloalkyl is optionally substitutedwith one or more halo; and

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

each cc is independently 1, 2, 3, or 4;

each A² is independently:

wherein:

each R^(A1) is independently selected from cyano, nitro, SOR⁴, SO₂R⁴,-alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl,(halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl,wherein each alkyl, heterocycle and cycloalkyl is optionally substitutedwith one or more halo;

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl;

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bband cc is 1, 2, 3, or 4;

each A³ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is substituted with one ormore R^(A1) groups, and which ring is optionally substituted with one ormore R^(A3) groups;

each A⁷ is independently:

wherein:

each H⁷ is independently a five-membered heteroaromatic ring, which H⁷is optionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3); and

each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O), C(═O)NR,CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each R isindependently selected from H or alkyl;

each A¹⁵ is independently:

wherein:

-   -   each H¹⁴ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic carbocycle which is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A¹⁶ is independently:

wherein:

each H¹⁵ is independently a fused unsaturated, partially unsaturated orsaturated tricyclic heterocycle that comprises at least one heteroatomin the ring system, which ring system is optionally substituted with oneor more groups independently selected from R^(A1) and R^(A3); and

-   -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A²⁰ is independently a 5 or 6 membered heteroaryl ring that isoptionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3);

each L⁹ is independently a fused-tetracyclic saturated, partiallyunsaturated, or aromatic heterocyclic ring system that is optionallysubstituted with one or more groups independently selected from oxo,halo, —R^(L9), —OR^(L9), —SR^(L9), —CF₃, —CCl₃, —OCF₃, —CN, —NO₂,—N(R^(L9))C(═O)R^(L9), —C(═O)R^(L9), —OC(═O)R^(L9), —C(O)OR^(L9),—C(═O)NR^(L9), —S(═O)R^(L9), —S(═O)₂OR^(L9), —S(═O)₂R^(L9),OS(═O)₂OR^(L9), —S(═O)₂NR^(L9), alkoxyalkyl, arylalkoxycarbonyl, halo,haloalkyl, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl;

each R^(L9) is independently —H, alkyl, aryl, arylalkyl, or heterocycle;and

R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

P^(1a) and P^(1b) are each independently selected from P⁰, P¹, P³, P⁵,P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyloxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle; each P¹⁰ is        independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and wherein each W^(1a) is substituted with one or more (e.g. 1,2, 3, or 4):

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

Y¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

X¹⁴ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P^(0a) and the other of P^(1a)and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

each P^(0a) is independently:

each R^(P5) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

ps is independently 0, 1, 2, 3, or 4;

pn is independently 0, 1, or 2;

po is independently 1, 2, or 3;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h)a)lkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R¹⁶ that are independently        selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and        —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a fused        three- to six-membered ring with an adjacent carbon atom,        wherein the three- to six-membered ring is optionally        substituted with one or two alkyl groups;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P^(0b) and the other of P^(1a)and P^(1b) is selected from P²¹, P³, P⁶, P⁷, P²⁸, P¹², P¹⁵ and P³⁸;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

each P^(0b) is independently:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb)

each R^(P5) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

ps is independently 0, 1, 2, 3, or 4;

pn is independently 0, 1, or 2;

each P²¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, —NR^(hh)R^(h), (NR^(hh)R^(h))carbonyl,        wherein each R^(h) is independently —H, alkyl, alkoxyamino,        aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P²⁸ is independently a ring of the formula:

wherein:

-   -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), where in two        R^(P13) groups are taken together with the carbon to which they        are attached and form a 4-6 membered heterocyclic ring;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P³⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is a compound of any one of formulae 1-25, 25b, 25c, and 25d asshown in Table 1, or a pharmaceutically acceptable salt or prodrugthereof.

In another embodiment the invention provides a compound of the inventionwhich is a compound of any one of formulae 26-102 as shown in Table 2,or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is a compound of any one of formulae 103-289 as shown in Table 3,or a pharmaceutically acceptable salt or prodrug thereof.

The invention also provides isotopically enriched compounds that arecompounds of the invention that comprise an enriched isotope at one ormore positions in the compound.

The present invention also provides a pharmaceutical compositioncomprising a compound of the invention and at least one pharmaceuticallyacceptable carrier.

The present invention also provides a pharmaceutical composition for usein treating disorders associated with HCV.

The present invention also provides a pharmaceutical composition furthercomprising an interferon or pegylated interferon.

The present invention also provides a pharmaceutical composition furthercomprising a nucleoside analog.

The present invention also provides for a pharmaceutical compositionwherein said nucleoside analogue is selected from ribavirin, viramidine,levovirin, an L-nucleoside, and isatoribine and said interferon isα-interferon or pegylated α-interferon.

The present invention also provides for a method of treating disordersassociated with hepatitis C, said method comprising administering to anindividual a pharmaceutical composition which comprises atherapeutically effective amount of a compound of the invention.

The present invention also provides a method of inhibiting HCV,comprising administering to a mammal afflicted with a conditionassociated with HCV activity, an amount of a compound of the invention,effective to inhibit HCV.

The present invention also provides a compound of the invention for usein medical therapy (e.g. for use in inhibiting HCV activity or treatinga condition associated with HCV activity), as well as the use of acompound of the invention for the manufacture of a medicament useful forinhibiting HCV or the treatment of a condition associated with HCVactivity in a mammal.

The present invention also provides synthetic processes and novelintermediates disclosed herein which are useful for preparing compoundsof the invention. Some of the compounds of the invention are useful toprepare other compounds of the invention.

In another aspect the invention provides a compound of the invention, ora pharmaceutically acceptable salt or prodrug thereof, for use in theprophylactic or therapeutic treatment of hepatitis C or a hepatitis Cassociated disorder.

In another aspect the invention provides a method of inhibiting HCVactivity in a sample comprising treating the sample with a compound ofthe invention.

Compounds of formula (I) have been found to possess useful activityagainst HCV genotypes 1 and 4. Compounds of formula (I) wherein W^(1a)is selected from structures 103-109 have been found to possess usefulactivity against HCV genotypes 1-4. Additionally certain compounds offormula (I) wherein W^(1a) is selected from structures 101-109 and atleast one of V^(1a) and V^(1b) is selected from:

are improved in potency against resistant variants in GT1 compared tothe corresponding compounds wherein V^(1a) and V^(1b) are each selectedfrom:

Accordingly, certain compounds of formula (I) wherein W^(1a) is selectedfrom structures 101-102 possess beneficial pharmacokinetic propertiesthat make them well suited to fulfil the current need for HCV agentswith such beneficial properties. Additionally compounds of formula (I)wherein W^(1a) is selected from structures 101, 102 and at least one ofV^(1a) and V^(1b) is selected from:

have been found to possess improved activity against HCV genotypes 2 and3 compared to the corresponding compounds wherein V^(1a) and V^(1b) areeach selected from:

Accordingly, certain compounds of formula (I) wherein W^(1a) is selectedfrom structures 101, 102 possess beneficial pharmacokinetic propertiesthat make them well suited to fulfil the current need for HCV agentswith such beneficial properties.

Compounds of formula (I) wherein W^(1a) is selected from structures 110,111, 112, 118 and 125 have been found to possess useful activity againstHCV genotypes 1-4. Additionally certain compounds of formula (I) whereinW^(1a) is selected from structures 110, 111, 112, 118 and 125 and atleast one of V^(1a) and V^(1b) is selected from:

are improved in potency against resistant variants in GT1 compared tothe corresponding compounds wherein V^(1a) and V^(1b) are each selectedfrom:

Accordingly, certain compounds of formula (I) wherein W^(1a) is selectedfrom structures 113, 114, 115, 116, 130 possess beneficialpharmacokinetic properties that make them well suited to fulfil thecurrent need for HCV agents with such beneficial properties.

Additionally certain compounds of formula (I) wherein W^(1a) is selectedfrom structures 113, 114, 115, 116, 130 and at least one of V^(1a) andV^(1b) is selected from:

are improved in potency against resistant variants in GT1 compared tothe corresponding compounds wherein V^(1a) and V^(1b) are each selectedfrom:

Additionally certain compounds of formula (I) wherein W^(1a) is selectedfrom structures 120-123 and at least one of V^(1a) and V^(1b) isselected from:

are improved in potency against resistant variants in GT1 compared tothe corresponding compounds wherein V^(1a) and V^(1b) are each selectedfrom:

Compounds of formula (I) wherein W^(1a) is selected from structure XX1been found to possess useful activity against HCV genotypes 1-4.Additionally certain compounds of formula (I) wherein W^(1a) is selectedfrom structures XX1 and at least one of V^(1a) and V^(1b) is selectedfrom:

are improved in potency against resistant variants in GT1 compared tothe corresponding compounds wherein V^(1a) and V^(1b) are each selectedfrom:

It has been further found that certain compounds of formula (I) withparticular W^(1a) groups have improved potency in genotypes 2, 2a and 2b(“GT2”, “GT2a”, and “GT2b”) when a methionine is present at the residue31 position of NS5A (“with M31 present”) (in the data tables herein theGT2a J6 replicon clone and the GT2b replicon have the more resistant M31residue present and the GT2a JFH replicon clone has the less resistantL31 residue). These certain compounds of formula (I) also can haveimproved potency against some resistant mutants in genotype 1 and othergenotypes. One such example of a resistant mutant in genotype 1a iswhere residue 30 has been changed from Q to R (Q30R). This mutant isrepresented in the data tables. Enhanced potencies can be furtherimproved when the particular W^(1a) groups are combined with certainselect P groups, or select V groups, and/or select E or R⁹ groupsindependently as described below.

Compounds possessing enhanced potency against GT2a, GT2b (both with M31present) and against some resistant variants in genotype 1 and othergenotypes include those where W^(1a) is selected from structures 103,105, 111, and 118.

Included are particular compounds of formula (I) wherein W^(1a) isselected from structure 103 of the formula:

wherein X³ is —CH₂—CH₂—, —CH₂—O—, or —O—CH₂—; and Y³ is —CH₂—CH₂—,—CH₂—O—, —O—CH₂—, or —CH═CH—. Further included are compounds whereW^(1a) is:

Further included are compounds where W^(1a) is:

Also included are particular compounds of formula (I) wherein W^(1a) isselected from structure 118 of the formula:

wherein X¹⁸ is —CH═CH—, —CH₂CH₂—, or —OCH₂—; and Y¹⁸ is phenyl. Furtherincluded are compounds where W^(1a) is:

Also included are particular compounds of formula (I) wherein W^(1a) isselected from structure 111 of the formula:

wherein X¹¹ is —CH₂—CH₂—, —O—CH₂—, or —CH═CH—; and Y¹¹ is —CH═CH—,—O—CH₂—.Further included are compounds where W^(1a) is:

Further included are compounds where W^(1a) is:

Also included are particular compounds of formula (I) wherein W^(1a) isselected from structure 105 of the formula:

wherein Y⁵ is —O—CH₂—, or —CH₂—O—; and X⁵ is —CH₂—CH₂— or —CH═CH—.Further included are compounds where W^(1a) is:

Further included are compounds where W^(1a) is:

Further included are compounds where W^(1a) is:

Additionally, when combined with P groups, V groups, and/or E or R⁹groups independently selected from groups described below, certaincompounds of formula (I) wherein W^(1a) is structure 130 can haveimproved potency in GT2a and GT2b (both with M31):

The observed enhanced potencies against GT2a, GT2b (both with M31present) and against some resistant variants in genotype 1 and othergenotypes can be further improved when the particular W^(1a) groupsdescribed above are combined with certain select P groups, or select Vgroups, and/or select E or R⁹ groups as described below.

One select combination group are those compounds wherein V^(1a) isselected from:

In particular, enhanced potency is observed when at least one V^(1a) isselected from:

Another select combination group are those compounds wherein P^(1a) andP^(1b) are selected from:

Particularly beneficial in providing enhanced potency against GT2a, GT2b(both with M31 present) and against some resistant variants in genotype1 and other genotypes are compounds where P^(1a) or P^(1b) is selectedfrom:

Other select combination groups include those where P^(1a) is:

and V^(1a) is selected from:

Other select combination groups include those where P^(1b) is:

and V^(1b) is selected from:

Other select combination groups include those where P^(1a) is:

and V^(1a) is selected from:

Other select combination groups include those where P^(1b) is:

and the V^(1b) is selected from:

Other select combination groups include those where P^(1a) is:

and the V^(1a) is,

Other select combination groups include those where P^(1b) is:

and the V^(1b) is,

Other select combination groups include those where P^(1a) is:

and V^(1a) is,

Other select combination groups include those where P^(1b) is:

and V^(1b) is,

Other select combination groups include those where P^(1a) is:

and V^(1a) is selected from:

Other select combination groups include those where P^(1b) is:

and V^(1b) is selected from:

Furthermore, additional potency against GT2a, GT2b (both with M31present) and against some resistant variants in genotype 1 and othergenotypes is observed in compounds wherein E^(1a)-V^(1a) taken togetherare R^(9a) or wherein E^(1b)-V^(1b) taken together are R^(9b), whereinR^(9a) or R^(9b) is selected from:

Accordingly, certain compounds of formula (I) possess beneficialpharmacological properties that make them well suited to fulfil thecurrent need for HCV agents with such beneficial properties.

In one embodiment the invention provides a compound having improvedinhibitory or pharmacokinetic properties, including enhanced activityagainst development of viral resistance, improved oral bioavailability,greater potency (for example, in inhibiting HCV activity) or extendedeffective half-life in vivo. Certain compounds of the invention may havefewer side effects, less complicated dosing schedules, or be orallyactive.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the present invention as defined by the embodiments.

Compounds of the Invention

The compounds of the invention exclude compounds heretofore known.However, it is within the invention to use compounds that previouslywere not known to have antiviral properties for antiviral purposes (e.g.to produce an anti-viral effect in an animal). With respect to theUnited States, the compounds or compositions herein exclude compoundsthat are anticipated under 35 USC §102 or that are obvious under 35 USC§103.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R¹” or “A³”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected.

“Absent”—Some groups are defined such that they can be absent. When agroup is absent it becomes a bond connector. The two groups that wouldotherwise be connected to that absent group are connected to each otherthrough a bond. For example, when W is absent, M is bonded to M.

“Alkyl” is C₁-C₁₈ hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms. Examples are methyl (Me, —CH₃), ethyl (Et,—CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and cyclopropylmethyl

“Alkenyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. Examples include, but are not limitedto, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl(—C₅H₇), and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. Examples include, but are not limited to,acetylenic (—C≡CH) and propargyl (—CH₂C≡CH).

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical of 1-18 carbon atoms, and having two monovalentradical centers derived by the removal of two hydrogen atoms from thesame or two different carbon atoms of a parent alkane. Typical alkyleneradicals include, but are not limited to, methylene (—CH₂—) 1,2-ethyl(—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), andthe like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkene. Typicalalkenylene radicals include, but are not limited to, 1,2-ethylene(—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkyne. Typicalalkynylene radicals include, but are not limited to, acetylene (—C≡C—),propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡CH).

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Typical aryl groups include, butare not limited to, radicals derived from benzene, substituted benzene,naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenylor alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

The term “polycarbocycle” refers to a saturated or unsaturatedpolycyclic ring system having from about 6 to about 25 carbon atoms andhaving two or more rings (e.g. 2, 3, 4, or 5 rings). The rings can befused and/or bridged to form the polycyclic ring system. For example,the term includes bicyclo[4,5], [5,5], [5,6] or [6,6] ring systems, aswell as the following bridged ring systems:

(i.e., [2.1.1], [2.2.1], [3.3.3], [4.3.1], [2.2.2], [4.2.2], [4.2.1],[4.3.2], [3.1.1], [3.2.1], [4.3.3], [3.3.2], [3.2.2] and [3.3.1]polycyclic rings, respectively) that can be linked to the remainder ofthe compound of formula (I) through any synthetically feasible position.Like the other polycarbocycles, these representative bicyclo and fusedring systems can optionally comprise one or more double bonds in thering system.

The term “polyheterocycle” refers to a polycarbocycle as defined herein,wherein one or more carbon atoms is replaced with a heteroatom (e.g., O,S, S(O), S(O)₂, N⁺(O⁻)R_(x), or NR_(x)); wherein each R_(x) isindependently H, (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl,(C1-10)alkanoyl, S(O)₂NR_(n)R_(p), S(O)₂R_(x), or (C1-10)alkoxy, whereineach (C1-10)alkyl, (C2-10)alkenyl, (C2-10)alkynyl, (C1-10)alkanoyl, and(C1-10)alkoxy is optionally substituted with one or more halo).

“Substituted alkyl”, “substituted aryl”, and “substituted arylalkyl”mean alkyl, aryl, and arylalkyl respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to: halo(e.g. F, Cl, Br, I), —R, —OR, —SR, —NR₂, —CF₃, —CCl₃, —OCF₃, —CN, —NO₂,—N(R)C(═O)R, —C(═O)R, —OC(═O)R, —C(O)OR, —C(═O)NRR, —S(═O)R, —S(═O)₂OR,—S(═O)₂R, —OS(═O)₂OR, —S(═O)₂NRR, and each R is independently —H, alkyl,aryl, arylalkyl, or heterocycle. Alkylene, alkenylene, and alkynylenegroups may also be similarly substituted.

The term “optionally substituted” in reference to a particular moiety ofthe compound of formula I, (e.g., an optionally substituted aryl group)refers to a moiety having 0, 1, 2, or more substituents.

The symbol “

” in a ring structure means that a bond is a single or double bond. In anon-limiting example,

can be

“Haloalkyl” as used herein includes an alkyl group substituted with oneor more halogens (e.g. F, Cl, Br, or I). Representative examples ofhaloalkyl include trifluoromethyl, 2,2,2-trifluoroethyl, and2,2,2-trifluoro-1-(trifluoromethyl)ethyl.

“Heterocycle” or “heterocyclyl” as used herein includes by way ofexample and not limitation these heterocycles described in Paquette, LeoA.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, NewYork, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistryof Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons,New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment ofthe invention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S). The term heterocycle also includes“heteroaryl” which is a heterocycle wherein at least one heterocyclicrings is aromatic.

Examples of heterocycles include by way of example and not limitationpyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring havingup to about 25 carbon atoms. Typically, a carbocycle has about 3 to 7carbon atoms as a monocycle, about 7 to 12 carbon atoms as a bicycle,and up to about 25 carbon atoms as a polycycle. Monocyclic carbocyclestypically have 3 to 6 ring atoms, still more typically 5 or 6 ringatoms. Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g.,arranged as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo[5,6] or [6,6] system. The termcarbocycle includes “cycloalkyl” which is a saturated or unsaturatedcarbocycle. Examples of monocyclic carbocycles include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes (D and L) or (Rand S) are used to denote the absolute configuration of the moleculeabout its chiral center(s). The prefixes d and l or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with (−) or l meaning that the compound is levorotatory. Acompound prefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity. The inventionincludes all stereoisomers of the compounds described herein.

The term “heterocyclylsulfonyl,” as used herein, refers to hetercyclylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “heteroarylsulfonyl,” as used herein, refers to heteroarylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “alkyloxy,” as used herein, refers to an alkyl group attachedto the parent molecular moiety through an oxygen atom.

The term “alkoxyalkyloxy,” as used herein, refers to an alkyloxy groupsubstituted with one, two, or three alkoxy groups.

The term “haloalkoxyalkyloxy,” as used herein, refers to an alkyloxygroup substituted with one, two, or three haloalkoxy groups.

The term “cycloalkyloxyalkyloxy,” as used herein, refers to an alkyloxygroup substituted with one, two, or three cycloalkyloxy groups.

The term “aryloxyalkyloxy,” as used herein, refers to an alkyloxy groupsubstituted with one, two, or three aryloxy groups.

The term “heteroaryloxyalkyloxy,” as used herein, refers to an alkyloxygroup substituted with one, two, or three heteroaryloxy groups.

The term “heterocyclyloxyalkyloxy,” as used herein, refers to analkyloxy group substituted with one, two, or three heterocyclyloxygroups.

The term “cyanoalkyloxy,” as used herein, refers to an alkyloxy groupsubstituted with one, two, or three cyano groups.

The term “cyanocycloalkyloxy,” as used herein, refers to a cycloalkyloxygroup substituted with one, two, or three cyano groups.

The term “haloalkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three haloalkoxy groups.

The term “amino,” as used herein, refers to —NH₂.

The term “alkylamino,” as used herein, refers to an amino groupsubstituted with one alkyl group (i.e. —NH(alkyl)).

The term “dialkylamino,” as used herein, refers to an amino groupsubstituted with two alkyl groups (i.e. —N(alkyl)₂).

The term “aminoalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three amino groups.

The term “alkylaminoalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkylamino groups.

The term “dialkylaminoalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three dialkylamino groups.

The term “alkoxyamino,” as used herein, refers to an amino groupsubstituted with one alkoxy group.

The term “sulfonylalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one SO₃H group.

Specific Definitions for Groups A⁰, P⁰, V⁰, Z⁰, and E⁰

For the groups A⁰, P⁰, V⁰, Z⁰, and E⁰ the following definitions apply.These definitions also apply for all other A, P, V, Z, and E groupsunless those groups are otherwise defined herein.

Unless stated otherwise, all aryl, cycloalkyl, and heterocyclyl groupsof the present disclosure may be substituted as described in each oftheir respective definitions. For example, the aryl part of an arylalkylgroup may be substituted as described in the definition of the term‘aryl’.

The term “alkenyl,” as used herein, refers to a straight or branchedchain group of two to six carbon atoms containing at least onecarbon-carbon double bond.

The term “alkenyloxy,” as used herein, refers to an alkenyl groupattached to the parent molecular moiety through an oxygen atom.

The term “alkenyloxycarbonyl,” as used herein, refers to an alkenyloxygroup attached to the parent molecular moiety through a carbonyl group.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkoxy groups.

The term “alkoxyalkylcarbonyl,” as used herein, refers to an alkoxyalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “alkoxyalkylcarbonylalkyl,” as used herein, refers to an alkylgroup substituted with one, two, or three alkoxyalkylcarbonyl groups.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkoxycarbonylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkoxycarbonyl groups.

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon containing from one tosix carbon atoms.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylcarbonylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkylcarbonyl groups.

The term “alkylcarbonyloxy,” as used herein, refers to an alkylcarbonylgroup attached to the parent molecular moiety through an oxygen atom.

The term “alkylsulfanyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfur atom.

The term “alkylsulfanylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three alkylsulfanyl groups.

The term “alkylsulfonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfonyl group.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclicfused ring system wherein one or both of the rings is a phenyl group.Bicyclic fused ring systems consist of a phenyl group fused to a four-to six-membered aromatic or non-aromatic carbocyclic ring. The arylgroups of the present disclosure can be attached to the parent molecularmoiety through any substitutable carbon atom in the group.Representative examples of aryl groups include, but are not limited to,indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The arylgroups of the present disclosure are optionally substituted with one,two, three, four, or five substituents independently selected fromalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second arylgroup, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy,haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo,and —P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro.

The term “arylalkenyl,” as used herein, refers to an alkenyl groupsubstituted with one, two, or three aryl groups.

The term “arylalkoxy,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkoxy group.

The term “arylalkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three arylalkoxy groups.

The term “arylalkoxyalkylcarbonyl,” as used herein, refers to anarylalkoxyalkyl group attached to the parent molecular moiety through acarbonyl group.

The term “arylalkoxyalkylcarbonylalkyl,” as used herein, refers to analkyl group substituted with one, two, or three arylalkoxyalkylcarbonylgroups.

The term “arylalkoxycarbonyl,” as used herein, refers to an arylalkoxygroup attached to the parent molecular moiety through a carbonyl group.

The term “arylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three aryl groups. The alkyl part of thearylalkyl is further optionally substituted with one or two additionalgroups independently selected from alkoxy, alkylcarbonyloxy, halo,haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and —NR^(c)R^(d), whereinthe heterocyclyl is further optionally substituted with one or twosubstituents independently selected from alkoxy, alkyl, unsubstitutedaryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo,haloalkoxy, haloalkyl, hydroxy, and —NR^(X)R^(Y);

The term “arylalkylcarbonyl,” as used herein, refers to an arylalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “arylcarbonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “aryloxy,” as used herein, refers to an aryl group attached tothe parent molecular moiety through an oxygen atom.

The term “aryloxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three aryloxy groups.

The term “aryloxycarbonyl,” as used herein, refers to an aryloxy groupattached to the parent molecular moiety through a carbonyl group.

The term “arylsulfanyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a sulfur atom.

The term “arylsulfonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a sulfonyl group.

The terms “Cap” and “cap” as used herein, refer to the group which isplaced on the nitrogen atom of the terminal nitrogen-containing ring. Itshould be understood that “Cap” or “cap” can refer to the reagent usedto append the group to the terminal nitrogen-containing ring or to thefragment in the final product.

The term “carbonyl,” as used herein, refers to —C(═O)—.

The term “carboxy,” as used herein, refers to —CO₂H.

The term “carboxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three carboxy groups.

The term “cyano,” as used herein, refers to —CN.

The term “cyanoalkyl” as used herein, refers to an alkyl group having atleast one —CN substituent.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,hydrocarbon ring system having three to seven carbon atoms and zeroheteroatoms. Representative examples of cycloalkyl groups include, butare not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. Thecycloalkyl groups of the present disclosure are optionally substitutedwith one, two, three, four, or five substituents independently selectedfrom alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy, hydroxyalkyl, nitro, and —NR^(x)R^(y) wherein thearyl and the heterocyclyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.

The term “(cycloalkyl)alkenyl,” as used herein, refers to an alkenylgroup substituted with one, two, or three cycloalkyl groups.

The term “(cycloalkyl)alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three cycloalkyl groups. The alkyl part ofthe (cycloalkyl)alkyl is further optionally substituted with one or twogroups independently selected from hydroxy and —NR^(c)R^(d).

The term “cycloalkyloxy,” as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “cycloalkyloxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three cycloalkyloxy groups.

The term “cycloalkylsulfonyl,” as used herein, refers to a cycloalkylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “formyl,” as used herein, refers to —CHO.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, orI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkoxycarbonyl,” as used herein, refers to a haloalkoxygroup attached to the parent molecular moiety through a carbonyl group.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “haloalkylsulfanyl,” as used herein, refers to a haloalkylgroup attached to the parent molecular moiety through a sulfur atom.

The term “heterocyclyl,” as used herein, refers to a four-, five-, six-,or seven-membered ring containing one, two, three, or four heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Thefour-membered ring has zero double bonds, the five-membered ring haszero to two double bonds, and the six- and seven-membered rings havezero to three double bonds. The term “heterocyclyl” also includesbicyclic groups in which the heterocyclyl ring is fused to anothermonocyclic heterocyclyl group, or a four- to six-membered aromatic ornon-aromatic carbocyclic ring; as well as bridged bicyclic groups suchas 7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oc-2-tyl, and2-azabicyclo[2.2.2]oc-3-tyl. The heterocyclyl groups of the presentdisclosure can be attached to the parent molecular moiety through anycarbon atom or nitrogen atom in the group. Examples of heterocyclylgroups include, but are not limited to, benzothienyl, furyl, imidazolyl,indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl,piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl,pyrrolopyridinyl, pyrrolyl, thiazolyl, thienyl, thiomorpholinyl,7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oc-2-tyl, and2-azabicyclo[2.2.2]oc-3-tyl. The heterocyclyl groups of the presentdisclosure are optionally substituted with one, two, three, four, orfive substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl, the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro.

The term “heterocyclylalkenyl,” as used herein, refers to an alkenylgroup substituted with one, two, or three heterocyclyl groups.

The term “heterocyclylalkoxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an alkoxy group.

The term “heterocyclylalkoxycarbonyl,” as used herein, refers to aheterocyclylalkoxy group attached to the parent molecular moiety througha carbonyl group.

The term “heterocyclylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three heterocyclyl groups. The alkyl partof the heterocyclylalkyl is further optionally substituted with one ortwo additional groups independently selected from alkoxy,alkylcarbonyloxy, aryl, halo, haloalkoxy, haloalkyl, hydroxy, and—NR^(c)R^(d), wherein the aryl is further optionally substituted withone or two substituents independently selected from alkoxy, alkyl,unsubstituted aryl, unsubstituted arylalkoxy, unsubstitutedarylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and—NR^(X)R^(Y).

The term “heterocyclylalkylcarbonyl,” as used herein, refers to aheterocyclylalkyl group attached to the parent molecular moiety througha carbonyl group.

The term “heterocyclylcarbonyl,” as used herein, refers to aheterocyclyl group attached to the parent molecular moiety through acarbonyl group.

The term “heterocyclylcarbonylalkyl,” as used herein, refers to an alkylgroup substituted with one, two, or three heterocyclylcarbonyl groups.

The term “heterocyclyloxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an oxygen atom.

The term “heterocyclyloxyalkyl,” as used herein, refers to an alkylgroup substituted with one, two, or three heterocyclyloxy groups.

The term “heterocyclyloxycarbonyl,” as used herein, refers to aheterocyclyloxy group attached to the parent molecular moiety through acarbonyl group.

The term “hydroxy,” as used herein, refers to —OH.

The term “hydroxyalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three hydroxy groups.

The term “hydroxyalkylcarbonyl,” as used herein, refers to ahydroxyalkyl group attached to the parent molecular moiety through acarbonyl group.

The term “nitro,” as used herein, refers to —NO₂.

The term “—NR^(a)R^(b),” as used herein, refers to two groups, R^(a) andR^(b), which are attached to the parent molecular moiety through anitrogen atom. R^(a) and R^(b) are independently selected from hydrogen,alkenyl, and alkyl.

The term “(NR^(a)R^(b))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(a)R^(b) groups.

The term “(NR^(a)R^(b))carbonyl,” as used herein, refers to an—NR^(a)R^(b) group attached to the parent molecular moiety through acarbonyl group.

The term “—NR^(c)R^(d),” as used herein, refers to two groups, R^(c) andR^(d), which are attached to the parent molecular moiety through anitrogen atom. R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “(NR^(c)R^(d))alkenyl,” as used herein, refers to an alkenylgroup substituted with one, two, or three —NR^(c)R^(d) groups.

The term “(NR^(c)R^(d))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(c)R^(d) groups. The alkyl partof the (NR^(c)R^(d))alkyl is further optionally substituted with one ortwo additional groups selected from alkoxy, alkoxyalkylcarbonyl,alkoxycarbonyl, alkylsulfanyl, arylalkoxyalkylcarbonyl, carboxy,heterocyclyl, heterocyclylcarbonyl, hydroxy, and (NR^(e)R^(f))carbonyl;wherein the heterocyclyl is further optionally substituted with one,two, three, four, or five substituents independently selected fromalkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “(NR^(c)R^(d))carbonyl,” as used herein, refers to an—NR^(c)R^(d) group attached to the parent molecular moiety through acarbonyl group.

The term “—NR^(e)R^(f),” as used herein, refers to two groups, R^(e) andR^(f), which are attached to the parent molecular moiety through anitrogen atom. R^(e) and R^(f) are independently selected from hydrogen,alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstitutedcycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstitutedheterocyclyl, unsubstituted heterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and—(NR^(X)R^(Y))carbonyl.

The term “(NR^(e)R^(f))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(e)R^(f) groups.

The term “(NR^(e)R^(f))alkylcarbonyl,” as used herein, refers to an(NR^(e)R^(f))alkyl group attached to the parent molecular moiety througha carbonyl group.

The term “(NR^(e)R^(f))carbonyl,” as used herein, refers to an—NR^(e)R^(f) group attached to the parent molecular moiety through acarbonyl group.

The term “(NR^(e)R^(f))sulfonyl,” as used herein, refers to an—NR^(e)R^(f) group attached to the parent molecular moiety through asulfonyl group.

The term “—NR^(X)R^(Y),” as used herein, refers to two groups, R^(X) andR^(Y), which are attached to the parent molecular moiety through anitrogen atom. R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl.

The term “(NR^(X)R^(Y))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(X)R^(Y) groups.

The term “oxo,” as used herein, refers to ═O.

The term “sulfonyl,” as used herein, refers to —SO₂—.

The term “trialkylsilyl,” as used herein, refers to —SiR₃, wherein R isalkyl. The R groups may be the same or different

The term “trialkylsilylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three trialkylsilyl groups.

The term “trialkylsilylalkoxy,” as used herein, refers to atrialkylsilylalkyl group attached to the parent molecular moiety throughan oxygen atom.

The term “trialkylsilylalkoxyalkyl,” as used herein, refers to an alkylgroup substituted with one, two, or three trialkylsilylalkoxy groups.

The “P” groups (eg P^(1a), P^(1b), P⁰, etc) defined for formula (I)herein have one bond to a —C(═O)— of formula (I) and one bond to aW^(1a) group. It is to be understood that a nitrogen of the P group isconnected to the —C(═O)— group of formula (I) and that a carbon of the Pgroup is connected to the W^(1a) group.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes (D and L) or (Rand S) are used to denote the absolute configuration of the moleculeabout its chiral center(s). The prefixes d and l or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with (−) or l meaning that the compound is levorotatory. Acompound prefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity. The inventionincludes all stereoisomers of the compounds described herein.

Prodrugs

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates a compound of theinvention that inhibits HCV activity (“the active inhibitory compound”).The compound may be formed from the prodrug as a result of: (i)spontaneous chemical reaction(s), (ii) enzyme catalyzed chemicalreaction(s), (iii) photolysis, and/or (iv) metabolic chemicalreaction(s).

“Prodrug moiety” refers to a labile functional group which separatesfrom the active inhibitory compound during metabolism, systemically,inside a cell, by hydrolysis, enzymatic cleavage, or by some otherprocess (Bundgaard, Hans, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development (1991), P. Krogsgaard-Larsen andH. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymeswhich are capable of an enzymatic activation mechanism with the prodrugcompounds of the invention include, but are not limited to, amidases,esterases, microbial enzymes, phospholipases, cholinesterases, andphosphases. Prodrug moieties can serve to enhance solubility, absorptionand lipophilicity to optimize drug delivery, bioavailability andefficacy. A prodrug moiety may include an active metabolite or drugitself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂OC(═O)R⁹⁹ and acyloxymethyl carbonates—CH₂OC(═O)OR⁹⁹ where R⁹⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al. (1983) J Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.Subsequently, the acyloxyalkyl ester was used to deliver phosphonicacids across cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂OC(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC) —CH₂OC(═O)OC(CH₃)₃.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to aphosphate have also been described (Khamnei and Torrence, (1996) J Med.Chem. 39:4109-4115). Benzyl esters are reported to generate parentphosphonic acids. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g., esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatephosphoric acid and a quinone methide intermediate. Examples of thisclass of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc.Perkin Trans. 112345; Glazier WO 91/19721. Still other benzylic prodrugshave been described containing a carboxylic ester-containing groupattached to the benzylic methylene (Glazier WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria etal. (1996) J. Med. Chem. 39: 4958).

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g., alcohols, bephysiologically acceptable, although in general it is more desirable ifthe products are pharmacologically innocuous.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. PGs do not need to be, and generally are not, the same if thecompound is substituted with multiple PG. In general, PG will be used toprotect functional groups such as carboxyl, hydroxyl, thio, or aminogroups and to thus prevent side reactions or to otherwise facilitate thesynthetic efficiency. The order of deprotection to yield freedeprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) include“ether- or ester-forming groups”. Ether- or ester-forming groups arecapable of functioning as chemical protecting groups in the syntheticschemes set forth herein. However, some hydroxyl and thio protectinggroups are neither ether- nor ester-forming groups, as will beunderstood by those skilled in the art, and are included with amides,discussed below.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,New York, 1994), which is incorporated by reference in its entiretyherein. In particular Chapter 1, Protecting Groups: An Overview, pages1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3,Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl ProtectingGroups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages155-184. For protecting groups for carboxylic acid, phosphonic acid,phosphonate, sulfonic acid and other protecting groups for acids seeGreene as set forth below.

By way of example and not limitation, R¹, R³, R^(A1), R^(A3), and X^(A)are recursive substituents in certain embodiments. Typically, each ofthese may independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11,10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. Moretypically, each of these may independently occur 12 or fewer times in agiven embodiment. Whenever a compound described herein is substitutedwith more than one of the same designated group, e.g., “R¹” or “R³”,then it will be understood that the groups may be the same or different,i.e., each group is independently selected. Wavy lines indicate the siteof covalent bond attachments to the adjoining groups, moieties, oratoms.

In one embodiment of the invention, the compound is in an isolated andpurified form. Generally, the term “isolated and purified” means thatthe compound is substantially free from biological materials (e.g.blood, tissue, cells, etc.). In one specific embodiment of theinvention, the term means that the compound or conjugate of theinvention is at least about 50 wt. % free from biological materials; inanother specific embodiment, the term means that the compound orconjugate of the invention is at least about 75 wt. % free frombiological materials; in another specific embodiment, the term meansthat the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, theterm means that the compound or conjugate of the invention is at leastabout 98 wt. % free from biological materials; and in anotherembodiment, the term means that the compound or conjugate of theinvention is at least about 99 wt. % free from biological materials. Inanother specific embodiment, the invention provides a compound orconjugate of the invention that has been synthetically prepared (e.g.,ex vivo).

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiralcarbon or phosphorus atoms. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures are separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

Examples of physiologically acceptable salts of the compounds of theinvention include salts derived from an appropriate base, such as analkali metal (for example, sodium), an alkaline earth metal (forexample, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl).Physiologically acceptable salts of a hydrogen atom or an amino groupinclude salts of organic carboxylic acids such as acetic, benzoic,lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, sulfuric, phosphoricand sulfamic acids. Physiologically acceptable salts of a compound of ahydroxy group include the anion of said compound in combination with asuitable cation such as Na⁺ and NX₄ ⁺ (wherein X is independentlyselected from H or a C₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will typically be physiologically acceptable, i.e. they willbe salts derived from a physiologically acceptable acid or base.However, salts of acids or bases which are not physiologicallyacceptable may also find use, for example, in the preparation orpurification of a physiologically acceptable compound. All salts,whether or not derived form a physiologically acceptable acid or base,are within the scope of the present invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines, or to acidic groups. Finally,it is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the natural orunnatural amino acids are suitable, especially the naturally-occurringamino acids found as protein components, although the amino acidtypically is one bearing a side chain with a basic or acidic group,e.g., lysine, arginine or glutamic acid, or a neutral group such asglycine, serine, threonine, alanine, isoleucine, or leucine.

Specific Embodiments

In one specific embodiment of the invention the compound of formula (I)is not:

In one specific embodiment of the invention the compound of formula (I)is not:

In one specific embodiment of the invention the compound of formula (I)is not:

Methods of Inhibition of HCV

Another aspect of the invention relates to methods of inhibiting theactivity of HCV comprising the step of treating a sample suspected ofcontaining HCV with a compound or composition of the invention.

Compounds of the invention may act as inhibitors of HCV, asintermediates for such inhibitors or have other utilities as describedbelow. The inhibitors will generally bind to locations on the surface orin a cavity of the liver. Compounds binding in the liver may bind withvarying degrees of reversibility. Those compounds binding substantiallyirreversibly are ideal candidates for use in this method of theinvention. Once labeled, the substantially irreversibly bindingcompounds are useful as probes for the detection of HCV. Accordingly,the invention relates to methods of detecting NS3 in a sample suspectedof containing HCV comprising the steps of: treating a sample suspectedof containing HCV with a composition comprising a compound of theinvention bound to a label; and observing the effect of the sample onthe activity of the label. Suitable labels are well known in thediagnostics field and include stable free radicals, fluorophores,radioisotopes, enzymes, chemiluminescent groups and chromogens. Thecompounds herein are labeled in conventional fashion using functionalgroups such as hydroxyl or amino. In one embodiment the inventionprovides a compound of any one of formulae (I)-(XIII) that comprises orthat is bound or linked to one or more detectable labels. Within thecontext of the invention samples suspected of containing HCV includenatural or man-made materials such as living organisms; tissue or cellcultures; biological samples such as biological material samples (blood,serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissuesamples, and the like); laboratory samples; food, water, or air samples;bioproduct samples such as extracts of cells, particularly recombinantcells synthesizing a desired glycoprotein; and the like. Typically thesample will be suspected of containing HCV. Samples can be contained inany medium including water and organic solvent/water mixtures. Samplesinclude living organisms such as humans, and man made materials such ascell cultures.

The treating step of the invention comprises adding the compound of theinvention to the sample or it comprises adding a precursor of thecomposition to the sample. The addition step comprises any method ofadministration as described above.

If desired, the activity of HCV after application of the compound can beobserved by any method including direct and indirect methods ofdetecting HCV activity. Quantitative, qualitative, and semiquantitativemethods of determining HCV activity are all contemplated. Typically oneof the screening methods described above are applied, however, any othermethod such as observation of the physiological properties of a livingorganism are also applicable.

Many organisms contain HCV. The compounds of this invention are usefulin the treatment or prophylaxis of conditions associated with HCVactivation in animals or in man.

However, in screening compounds capable of inhibiting HCV activity itshould be kept in mind that the results of enzyme assays may not alwayscorrelate with cell culture assays. Thus, a cell based assay shouldtypically be the primary screening tool.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis of conditions associated with HCV activity.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provides compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

HCV Combination Therapy

In another embodiment, non-limiting examples of suitable combinationsinclude combinations of one or more compounds of the present inventionwith one or more interferons, ribavirin or its analogs, HCV NS3 proteaseinhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,nucleoside or nucleotide inhibitors of HCV NS5B polymerase,non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors,TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors,pharmacokinetic enhancers, and other drugs for treating HCV.

More specifically, one or more compounds of the present invention may becombined with one or more compounds selected from the group consistingof

1) interferons, e.g., pegylated rIFN-alpha 2b (PEG-Intron), pegylatedrIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a(Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative,Multiferon, subalin), interferon alfacon-1 (Infergen), interferonalpha-n1 (Wellferon), interferon alpha-n3 (Alferon), interferon-beta(Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510),albinterferon alpha-2b (Albuferon), IFN alpha-2b XL, BLX-883 (Locteron),DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen,PEGylated interferon lambda-1 (PEGylated IL-29), and belerofon,

2) ribavirin and its analogs, e.g., ribavirin (Rebetol, Copegus), andtaribavirin (Viramidine),

3) HCV NS3 protease inhibitors, e.g., boceprevir (SCH-503034, SCH-7),telaprevir (VX-950), TMC435350, BI-1335, BI-1230, MK-7009, VBY-376,VX-500, GS-9256, GS-9451, BMS-790052, BMS-605339, PHX-1766, AS-101,YH-5258, YH5530, YH5531, and ITMN-191,

4) alpha-glucosidase 1 inhibitors, e.g., celgosivir (MX-3253), Miglitol,and UT-231B,

5) hepatoprotectants, e.g., emericasan (IDN-6556), ME-3738, GS-9450(LB-84451), silibilin, and MitoQ,

6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase, e.g.,R1626, R7128 (R4048), IDX184, IDX-102, BCX-4678, valopicitabine(NM-283), and MK-0608,

7) non-nucleoside inhibitors of HCV NS5B polymerase, e.g., PF-868554,VCH-759, VCH-916, JTK-652, MK-3281, GS-9190, VBY-708, VCH-222, A848837,ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796(nesbuvir), GSK625433, BILN-1941, XTL-2125, and GS-9190,

8) HCV NS5A inhibitors, e.g., AZD-2836 (A-831), BMS-790052, and A-689,

9) TLR-7 agonists, e.g., imiquimod, 852A, GS-9524, ANA-773, ANA-975,AZD-8848 (DSP-3025), and SM-360320,

10) cyclophillin inhibitors, e.g., DEBIO-025, SCY-635, and NIM811,

11) HCV IRES inhibitors, e.g., MCI-067,

12) pharmacokinetic enhancers, e.g., BAS-100, SPI-452, PF-4194477,TMC-41629, GS-9350, GS-9585, and roxythromycin,

13) other drugs for treating HCV, e.g., thymosin alpha 1 (Zadaxin),nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex),KPE02003002, actilon (CPG-10101), GS-9525, KRN-7000, civacir, GI-5005,XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin,EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325,Bavituximab, MDX-1106 (ONO-4538), Oglufanide, and VX-497 (merimepodib).

In yet another embodiment, the present application disclosespharmaceutical compositions comprising a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, in combination with at least one additional therapeutic agent,and a pharmaceutically acceptable carrier or excipient.

According to the present invention, the therapeutic agent used incombination with the compound of the present invention can be any agenthaving a therapeutic effect when used in combination with the compoundof the present invention. For example, the therapeutic agent used incombination with the compound of the present invention can beinterferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymeraseinhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,non-nucleoside inhibitors of HCV, and other drugs for treating HCV.

In another embodiment, the present application provides pharmaceuticalcompositions comprising a compound of the present invention, or apharmaceutically acceptable salt, solvate, and/or ester thereof, incombination with at least one additional therapeutic agent selected fromthe group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha,infergen, rebif, locteron, AVI-005, PEG-infergen, pegylated IFN-beta,oral interferon alpha, feron, reaferon, intermax alpha, r-IFN-beta,infergen+actimmune, IFN-omega with DUROS, albuferon, rebetol, copegus,levovirin, VX-497, viramidine (taribavirin), A-831, A-689, NM-283,valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608,NM-107, R7128, VCH-759, PF-868554, GSK625433, XTL-2125, SCH-503034(SCH-7), VX-950 (Telaprevir), ITMN-191, and BILN-2065, MX-3253(celgosivir), UT-231B, IDN-6556, ME 3738, MitoQ, and LB-84451,benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, andphenylalanine derivatives, zadaxin, nitazoxanide (alinea), BIVN-401(virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, bavituximab,oglufanide, PYN-17, KPE02003002, actilon (CPG-10101), KRN-7000, civacir,GI-5005, ANA-975 (isatoribine), XTL-6865, ANA 971, NOV-205, tarvacin,EHC-18, and NIM811 and a pharmaceutically acceptable carrier orexcipient.

In yet another embodiment, the present application provides acombination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of thepresent invention, or a pharmaceutically acceptable salt, solvate, orester thereof; and

b) a second pharmaceutical composition comprising at least oneadditional therapeutic agent selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors,alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleosideinhibitors of HCV, and other drugs for treating HCV, and combinationsthereof.

Combinations of the compounds of formula I and additional activetherapeutic agents may be selected to treat patients infected with HCVand other conditions such as HIV infections. Accordingly, the compoundsof formula I may be combined with one or more compounds useful intreating HIV, for example HIV protease inhibiting compounds,non-nucleoside inhibitors of HIV reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirinanalogs, NS3 protease inhibitors, NS5b polymerase inhibitors,alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleosideinhibitors of HCV, and other drugs for treating HCV.

More specifically, one or more compounds of the present invention may becombined with one or more compounds selected from the group consistingof 1) HIV protease inhibitors, e.g., amprenavir, atazanavir,fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir+ritonavir,nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), AG1859, DG35, L-756423,R00334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG17, PPL-100, 2) aHIV non-nucleoside inhibitor of reverse transcriptase, e.g.,capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150,and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355 BS, VRX 840773,UK-453,061, RDEA806, 3) a HIV nucleoside inhibitor of reversetranscriptase, e.g., zidovudine, emtricitabine, didanosine, stavudine,zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine,MIV-210, racivir (±-FTC), D-d4FC, emtricitabine, phosphazide, fozivudinetidoxil, fosalvudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461,abacavir+lamivudine, abacavir+lamivudine+zidovudine,zidovudine+lamivudine, 4) a HIV nucleotide inhibitor of reversetranscriptase, e.g., tenofovir, tenofovir disoproxilfumarate+emtricitabine, tenofovir disoproxilfumarate+emtricitabine+efavirenz, and adefovir, 5) a HIV integraseinhibitor, e.g., curcumin, derivatives of curcumin, chicoric acid,derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, zintevir (AR-177),L-870812, and L-870810, MK-0518 (raltegravir), BMS-707035, MK-2048,BA-011, BMS-538158, GSK364735C, 6) a gp41 inhibitor, e.g., enfuvirtide,sifuvirtide, FB006M, TRI-1144, SPC3, DES6, Locus gp41, CovX, and REP 9,7) a CXCR4 inhibitor, e.g., AMD-070, 8) an entry inhibitor, e.g., SP01A,TNX-355, 9) a gp120 inhibitor, e.g., BMS-488043 and BlockAide/CR, 10) aG6PD and NADH-oxidase inhibitor, e.g., immunitin, 10) a CCR5 inhibitor,e.g., aplaviroc, vicriviroc, INCB9471, PRO-140, INCB15050, PF-232798,CCR5mAb004, and maraviroc, 11) an interferon, e.g., pegylated rIFN-alpha2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha2a, consensus IFN alpha, infergen, rebif, locteron, AVI-005,PEG-infergen, pegylated IFN-beta, oral interferon alpha, feron,reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega withDUROS, and albuferon, 12) ribavirin analogs, e.g., rebetol, copegus,levovirin, VX-497, and viramidine (taribavirin) 13) NS5a inhibitors,e.g., A-831, A-689, and BMS-790052, 14) NS5b polymerase inhibitors,e.g., NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB1941, MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433, andXTL-2125, 15) NS3 protease inhibitors, e.g., SCH-503034 (SCH-7), VX-950(Telaprevir), ITMN-191, and BILN-2065, 16) alpha-glucosidase 1inhibitors, e.g., MX-3253 (celgosivir) and UT-231B, 17)hepatoprotectants, e.g., IDN-6556, ME 3738, MitoQ, and LB-84451, 18)non-nucleoside inhibitors of HCV, e.g., benzimidazole derivatives,benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives, 19)other drugs for treating Hepatitis C, e.g., zadaxin, nitazoxanide(alinea), BIVN-401 (virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065,bavituximab, oglufanide, PYN-17, KPE02003002, actilon (CPG-10101),KRN-7000, civacir, GI-5005, ANA-975 (isatoribine), XTL-6865, ANA 971,NOV-205, tarvacin, EHC-18, and NIM811, 19) pharmacokinetic enhancers,e.g., BAS-100 and SPI452, 20) RNAse H inhibitors, e.g., ODN-93 andODN-112, 21) other anti-HIV agents, e.g., VGV-1, PA-457 (bevirimat),ampligen, HRG214, cytolin, polymun, VGX-410, KD247, AMZ 0026, CYT 99007,A-221 HIV, BAY 50-4798, MDX010 (iplimumab), PBS 119, ALG889, andPA-1050040.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled (e.g., C¹⁴ or H³) compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites is done in thesame way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possess noHCV-inhibitory activity of their own.

Methods for determining stability of compounds in surrogategastrointestinal secretions are known.

Exemplary Methods of Making the Compounds of the Invention.

The invention also relates to methods of making the compositions of theinvention. The compositions are prepared by any of the applicabletechniques of organic synthesis. Many such techniques are well known inthe art. However, many of the known techniques are elaborated inCompendium of Organic Synthetic Methods (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., AdvancedOrganic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985),Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief(Pergamon Press, New York, 1993 printing). Other methods suitable forpreparing compounds of the invention are described in InternationalPatent Application Publication Number WO 2006/020276.

A number of exemplary methods for the preparation of the compositions ofthe invention are provided in the schemes and examples below. Thesemethods are intended to illustrate the nature of such preparations andare not intended to limit the scope of applicable methods.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

The terms “treated”, “treating”, “treatment”, and the like, when used inconnection with a chemical synthetic operation, mean contacting, mixing,reacting, allowing to react, bringing into contact, and other termscommon in the art for indicating that one or more chemical entities istreated in such a manner as to convert it to one or more other chemicalentities. This means that “treating compound one with compound two” issynonymous with “allowing compound one to react with compound two”,“contacting compound one with compound two”, “reacting compound one withcompound two”, and other expressions common in the art of organicsynthesis for reasonably indicating that compound one was “treated”,“reacted”, “allowed to react”, etc., with compound two. For example,treating indicates the reasonable and usual manner in which organicchemicals are allowed to react. Normal concentrations (0.01M to 10M,typically 0.1M to IM), temperatures (−100° C. to 250° C., typically −78°C. to 150° C., more typically −78° C. to 100° C., still more typically0° C. to 100° C.), reaction vessels (typically glass, plastic, metal),solvents, pressures, atmospheres (typically air for oxygen and waterinsensitive reactions or nitrogen or argon for oxygen or watersensitive), etc., are intended unless otherwise indicated. The knowledgeof similar reactions known in the art of organic synthesis is used inselecting the conditions and apparatus for “treating” in a givenprocess. In particular, one of ordinary skill in the art of organicsynthesis selects conditions and apparatus reasonably expected tosuccessfully carry out the chemical reactions of the described processesbased on the knowledge in the art.

Modifications of each of the exemplary schemes and in the Examples(hereafter “exemplary schemes”) leads to various analogs of the specificexemplary materials produce. The above-cited citations describingsuitable methods of organic synthesis are applicable to suchmodifications.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113, 3)283-302). Racemic mixtures of chiral compounds of the invention can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched substrate. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

SCHEMES AND EXAMPLES

General aspects of these exemplary methods are described below and inthe Examples. Each of the products of the following processes isoptionally separated, isolated, and/or purified prior to its use insubsequent processes.

A number of exemplary methods for the preparation of compounds of theinvention are provided herein, for example, in the Examples below. Thesemethods are intended to illustrate the nature of such preparations andare not intended to limit the scope of applicable methods. Certaincompounds of the invention can be used as intermediates for thepreparation of other compounds of the invention. In the exemplarymethods described herein, the fragment E-V— can also be written as R9-.PG represents a protecting group common for the given functional groupthat it is attached. The installation and removal of the protectinggroup can be accomplished using standard techniques, such as thosedescribed in Wuts, P. G. M., Greene, T. Protective Groups in OrganicSynthesis, 4th ed.; John Wiley & Sons, Inc.: Hoboken, N.J., 2007.

Scheme 1 shows a general synthesis of an E-V—C(═O)—P—W—P—C(═O)—V-Emolecule of the invention wherein, for illustrative purposes, E ismethoxycarbonylamino. The treatment of either 1a or 1c with one or twoequivalents respectively of methyl chloroformate under basic conditions(e.g. sodium hydroxide) provides the molecule 1b or 1d.

Scheme 2 shows a general synthesis of an E-V—C(═O)—P—W—P—C(═O)—V-Emolecule of the invention wherein, for illustrative purposes, P ispyrrolidine. Coupling of amine 2a with acid 2b is accomplished using apeptide coupling reagent (e.g. HATU) to afford 2c. Alternatively, amine2d is coupled with two equivalents of 2b under similar conditions toprovide 2e.

Scheme 3 shows a general synthesis of an E-V—C(═O)—P—W—P—C(═O)—V-Emolecule of the invention wherein, for illustrative purposes, W is afour aromatic ring unit constructed via a transition metal mediatedcross-coupling reaction. For illustrative purposes, the Suzuki reactionis employed to couple a boronic ester to either an aryl- orheteroarylbromide. Boronic ester 3b is coupled with an appropriatecoupling partner (e.g. 3a) using a palladium catalyst, such asPd(PPh3)4, to afford 3c. For each transition metal mediatedcross-coupling reaction, the roles of the nucleophile and electrophilecan be reversed to provide the same coupling product. Other transitionmetal mediated cross couplings that enable the construction of W, butemploy alternative coupling partners and reagents, include, but are notlimited to, the Negishi, Kumada, Stille, and Ullman couplings.

Scheme 4 shows a general synthesis of an E-V—C(═O)—P—W—P—C(═O)—V-Emolecule of the invention wherein, for illustrative purposes, W is afour aromatic ring unit constructed by the formation of a substitutedimidazole ring. The formation of the imidazole is accomplished bycoupling the acid 4b with an α-haloketone, such as α-bromoketone 4a,under basic conditions (e.g. Et₃N) to afford 4c. Alternatively, the acid4b is coupled with an α-aminoketone 4e, under amide formation conditions(e.g. EDC, Et₃N) to afford 4f. Reaction of 4c or 4f with an amine oramine salt (e.g. ammonium acetate) affords the imidazole containingmolecule 4d.

The formation of multiple imidazoles is performed in the same manner,starting with a bis-α-haloketone such as α-bromoketone 4g, to providemolecule 4d.

Scheme 5 shows a general synthesis of an E-V—C(═O)—P—W—P—C(═O)—V-Emolecule of the invention wherein, for illustrative purposes, W is athree or four aromatic ring unit constructed by the formation of asubstituted benzimidazole ring. The formation of the benzimidazole isaccomplished by coupling the acid 5b with an arylamine 5a, using apeptide coupling reagent such as HATU, to afford 5c. Cyclization of theamide 5c in the presence an acid (such as acetic acid) affords thebenzimidazole containing molecule 5d.

The formation of multiple benzimidazoles is performed in the samemanner, starting with a bis-diamine such as 5f, to provide molecule 5g.

Scheme 6 shows a general synthesis of an R¹—V—C(═O)—P—R² intermediatewherein, for illustrative purposes, P is pyrrolidine, R¹ is a genericgroup that is depicted as either -E or a amino protecting group, and R²is a generic group that is depicted as —W—P—C(═O)—V-E,—W—P—C(═O)—V-NH-PG, —W—P-NH-PG, or —W—NH-PG. Coupling of amine 6a (or6d, 6h, 6k) with acid 6b or 6e is accomplished using a peptide couplingreagent (e.g. HATU) to afford 6c (or 6f, 6g, 6i, 6j, 6l, 6m)respectively.

Scheme 7 shows a general synthesis of an E-V—C(═O)—R¹ intermediatewherein, for illustrative purposes, E is methoxycarbonylamino and R¹ isa generic group that is depicted as either —P—W—P—C(═O)—V-NH-PG,—P—W—P-PG, —P—W-PG, —P-PG, or —O-PG. Treatment of 7a (or 7c, 7e, 7g, 7i)with methyl chloroformate under basic conditions (e.g. sodium hydroxide)provides the molecule 7b (or 7d, 7f, 7h, 7j).

Scheme 8 shows a general synthesis of an R¹—P—R² intermediate wherein,for illustrative purposes, R¹ is —C(═O)—V-E or a protecting group and R²is a substituted imidazole. The formation of the imidazole isaccomplished by coupling the acid 8b or 8e with an α-haloketone, such asα-chloroketone 8a, under basic conditions (e.g. Et₃N) to afford 8c or8f. Alternatively, the acid 8b or 8e is coupled with an α-aminoketone8h, under amide formation conditions (e.g. EDC, Et₃N) to afford 8i or8j. Reaction of 8c (or 8f, 8i, 8j) with an amine or amine salt (e.g.ammonium acetate) affords the imidazole containing molecule 8d or 8g.

The formation of multiple imidazoles is performed in the same manner,starting with a bis-α-haloketone to provide the correspondingbis-imidazole.

Scheme 9 shows a general synthesis of an R¹—P—R² intermediate wherein,for illustrative purposes, R¹ is —C(═O)—V-E or a protecting group and R²is a substituted benzamidazole. The formation of the benzimidazole isaccomplished by coupling the acid 9b or 9e with an arylamine 9a, using apeptide coupling reagent such as HATU, to afford 9c or 9d. Cyclizationof the amide in the presence an acid (such as acetic acid) affords thebenzimidazole containing molecule 9d or 9g.

The formation of multiple benzimidazoles is performed in the samemanner, starting with a bis-diamine to provide the correspondingbis-benzamidazole.

Scheme 10 shows a general synthesis of an R¹—P—R² intermediate wherein,for illustrative purposes, R¹ is a protecting group and R² is asubstituted naphthamidazole. The formation of the naphthamidazole isaccomplished by coupling the acid 10b with an arylamine 10a, using apeptide coupling reagent such as HATU, to afford 10c. Cyclization of theamide in the presence an acid (such as acetic acid) affords thebenzimidazole containing molecule 10d.

The naphthamidazole can also be accomplished by coupling the acid 10b,where A represents 0 or CH₂, with an α-haloketone, such as α-bromoketone10e, under basic conditions (e.g. Et₃N) to afford 10f. Alternatively,the acid 8b is coupled with an α-aminoketone 10g, under amide formationconditions (e.g. EDC, Et₃N) to afford 10h. Reaction of 10f or 10h withan amine or amine salt (e.g. ammonium acetate) affords the imidazolecontaining molecule 10i. When A is CH₂, oxidation of 10i to 10d can beaccomplished by heating in the presence of MnO₂.

Scheme 11 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a four aromatic ring unitconstructed via a transition metal mediated cross-coupling reaction. Forillustrative purposes, the Suzuki reaction is employed to couple aboronic ester to either an aryl- or heteroarylbromide. Boronic ester 11bis coupled with an appropriate coupling partner (e.g. 11a) using apalladium catalyst, such as Pd(PPh3)4, to afford 11c. For eachtransition metal mediated cross-coupling reaction, the roles of thenucleophile and electrophile can be reversed to provide the samecoupling product. Other transition metal mediated cross couplings thatenable the construction of W, but employ alternative coupling partnersand reagents, include, but are not limited to, the Negishi, Kumada,Stille, and Ullman couplings.

Scheme 12 shows a general synthesis of an R¹—P—R² intermediate of theinvention wherein, for illustrative purposes, R¹ is a generic group thatis depicted as a protecting group and R² is a generic group that isdepicted as an aryl boronic ester. A transition metal-mediatedcross-coupling reaction is utilized to install the boronic ester.Treatment of the corresponding aryl bromide with a palladium catalyst,such as PdCl₂(dppf), and a boron source such as bis(pinacolato)diboronprovides the boronic ester 12b.

Scheme 13 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a three aromatic ring unitconstructed via a transition metal mediated cross-coupling reaction. Forillustrative purposes, W is constructed from a tricyclic aromatic ring,wherein X¹ and X² are independent halogens or halogen equivalents thatmay be suitably protected. For illustrative purposes, a transitionmetal-mediated cross-coupling reaction is utilized to install theboronic ester and the Suzuki reaction is employed to couple the boronicester to a heteroarylbromide. Treatment of the 13a or 13e with apalladium catalyst, such as PdCl₂(dppf), and a boron source such asbis(pinacolato)diboron provides the boronic ester 13b or 13f. Theboronic ester is coupled with an appropriate coupling partner (e.g. 13cor 13h) using a palladium catalyst, such as Pd(PPh3)4, to afford 13d or13i. For each transition metal mediated cross-coupling reaction, theroles of the nucleophile and electrophile can be reversed to provide thesame coupling product. Other transition metal mediated cross couplingsthat enable the construction of W, but employ alternative couplingpartners and reagents, include, but are not limited to, the Negishi,Kumada, Stille, and Ullman couplings.

Scheme 14 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a three aromatic ring unitconstructed via a transition metal mediated cross-coupling reaction. Forillustrative purposes, W is constructed from a tetracyclic aromaticring, wherein X¹ and X² are independent halogens or halogen equivalentsthat may be suitably protected. The construction of the tetracycliccompound 14b can be accomplished from a suitably functionalized biphenylintermediate (e.g. 14a) by activation with PBr₃ followed by treatmentwith a base, such as cesium carbonate. For illustrative purposes, atransition metal-mediated cross-coupling reaction is utilized to installthe boronic ester and the Suzuki reaction is employed to couple theboronic ester to a heteroarylbromide. Treatment of the 14b with apalladium catalyst, such as PdCl₂(dppf), and a boron source such asbis(pinacolato)diboron provides the boronic ester 14c. The boronic esteris coupled with an appropriate coupling partner (e.g. 14d) using apalladium catalyst, such as Pd(PPh3)4, to afford 14e. For eachtransition metal mediated cross-coupling reaction, the roles of thenucleophile and electrophile can be reversed to provide the samecoupling product. Other transition metal mediated cross couplings thatenable the construction of W, but employ alternative coupling partnersand reagents, include, but are not limited to, the Negishi, Kumada,Stille, and Ullman couplings.

Scheme 15 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a three aromatic ring unitconstructed via a transition metal mediated cyclization. Forillustrative purposes, W includes a tetracyclic aromatic ring.Metalation of 15a with either n-BuLi or i-PrMgCl, followed by treatmentwith 2-Chloro-N-methoxy-N-methyl-acetamide provides the α-haloketone15b. Treatment with an acid, such as 15c, under basic conditions (e.g.Et₃N) provides the ester 15d. Activation of 15e, and treatment with 15d,under basic conditions provides the ether 15f. Cyclization in thepresence of a transition metal catalyst, such as Pd(OAc)₂ provides 15g.Reaction of 15g with an amine or amine salt (e.g. ammonium acetate)affords the imidazole containing molecule 15h.

Scheme 16 shows a general synthesis of an E-V—C(═O)—P—W—P—C(═O)—V-Emolecule of the invention wherein, for illustrative purposes, W is athree aromatic ring unit constructed via a transition metal mediatedcross-coupling reaction. For illustrative purposes, the Suzuki reactionis employed to couple a boronic ester to either an aryl- orheteroarylbromide. Boronic ester 16b is coupled with an appropriatecoupling partner (e.g. 16a) using a palladium catalyst, such asPd(PPh3)4, to afford 16c. For each transition metal mediatedcross-coupling reaction, the roles of the nucleophile and electrophilecan be reversed to provide the same coupling product. Other transitionmetal mediated cross couplings that enable the construction of W, butemploy alternative coupling partners and reagents, include, but are notlimited to, the Negishi, Kumada, Stille, and Ullman couplings. For thepreparation of alternate three aromatic ring containing W groups, thisgeneral scheme can be applied through the choice of the appropriatecross coupling partners and reagents.

Scheme 17 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a three aromatic ring unitconstructed via a transition metal mediated cross-coupling reaction. Forillustrative purposes, the Suzuki reaction is employed to couple aboronic ester to either an aryl- or heteroarylbromide. Boronic ester 17bis coupled with an appropriate coupling partner (e.g. 17a) using apalladium catalyst, such as Pd(PPh₃)₄, to afford 17c. For eachtransition metal mediated cross-coupling reaction, the roles of thenucleophile and electrophile can be reversed to provide the samecoupling product. Other transition metal mediated cross couplings thatenable the construction of W, but employ alternative coupling partnersand reagents, include, but are not limited to, the Negishi, Kumada,Stille, and Ullman couplings. For the preparation of alternate threearomatic ring containing W groups, this general scheme can be appliedthrough the choice of the appropriate cross coupling partners andreagents.

Scheme 18 shows a general synthesis of an E-V—C(═O)—P—W—P—C(═O)—V-Emolecule of the invention wherein, for illustrative purposes, W is a twoaromatic ring unit constructed via a transition metal mediatedcross-coupling reaction. For illustrative purposes, the Suzuki reactionis employed to couple a boronic ester to either an aryl- orheteroarylbromide. Boronic ester 18b is coupled with an appropriatecoupling partner (e.g. 18a) using a palladium catalyst, such asPd(PPh3)4, to afford 18c. For each transition metal mediatedcross-coupling reaction, the roles of the nucleophile and electrophilecan be reversed to provide the same coupling product. Other transitionmetal mediated cross couplings that enable the construction of W, butemploy alternative coupling partners and reagents, include, but are notlimited to, the Negishi, Kumada, Stille, and Ullman couplings. For thepreparation of alternate two aromatic ring containing W groups, thisgeneral scheme can be applied through the choice of the appropriatecross coupling partners and reagents.

Scheme 19 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a two aromatic ring unitconstructed via a transition metal mediated cross-coupling reaction. Forillustrative purposes, the Suzuki reaction is employed to couple aboronic ester to either an aryl- or heteroarylbromide. Boronic ester 19bis coupled with an appropriate coupling partner (e.g. 19a) using apalladium catalyst, such as Pd(PPh₃)₄, to afford 19c. For eachtransition metal mediated cross-coupling reaction, the roles of thenucleophile and electrophile can be reversed to provide the samecoupling product. Other transition metal mediated cross couplings thatenable the construction of W, but employ alternative coupling partnersand reagents, include, but are not limited to, the Negishi, Kumada,Stille, and Ullman couplings. For the preparation of alternate twoaromatic ring containing W groups, this general scheme can be appliedthrough the choice of the appropriate cross coupling partners andreagents.

Scheme 20 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a two aromatic ring unitconstructed via a transition metal mediated cyclization. Alkylation ofphenol 20b with an alkyl bromide, such as 20a, provides the ether 20c.Cyclization of the aromatic rings in the presence of a palladiumcatalyst provides the compound 20d. Treatment of 20d with CuBr₂ providesthe α-haloketone 20e, which provides 20f upon addition of an acid underbasic conditions (e.g. Et₃N). Reaction of 20f with an amine or aminesalt (e.g. ammonium acetate) affords the imidazole containing molecule20g. Oxidation of 20g, 20i, or 20l can be accomplished by heating in thepresence of MnO₂ to provide 20h, 20j, or 20m, respectively. Conversionof 20g or 20h with a palladium catalyst, such as Pd₂dba₃ and X-Phos, anda boron source such as bis(pinacolato)diboron provides the boronic ester20i or 20j. The boronic ester is coupled with an appropriate couplingpartner (e.g. 20k) using a palladium catalyst, such as Pd(PPh₃)₄ orPdCl₂(dppf), to afford 20l or 20m. For each transition metal mediatedcross-coupling reaction, the roles of the nucleophile and electrophilecan be reversed to provide the same coupling product. Other transitionmetal mediated cross couplings that enable the construction of W, butemploy alternative coupling partners and reagents, include, but are notlimited to, the Negishi, Kumada, Stille, and Ullman couplings. For thepreparation of alternate two aromatic ring containing W groups, thisgeneral scheme can be applied through the appropriate choice of thestarting reagents.

Scheme 21 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a two aromatic ring unitconstructed via a transition metal mediated cyclization. Treatment of20d with an activated vinyl reagent (e.g. potassiumvinyltrifluoroborate) in the presence of a palladium catalyst (e.g.palladium acetate and S-Phos) provides the vinyl compound 21a.Conversion to the corresponding α-halo ketone can be accomplished bybromination with N-bromosuccinimide, followed by oxidation with MnO₂.Displacement of the α-halo ketone proceeds by the addition of an acidunder basic conditions (e.g. Et₃N). Bromination of 21d proceeds upontreatment with pyridinium tribromide, and is followed by the addition ofa second acid under basic conditions to provide the diester 21e.Reaction of 21e with an amine or amine salt (e.g. ammonium acetate)affords the imidazole containing molecule 21f. Oxidation of 21f can beaccomplished in the presence of MnO₂ to provide 21g.

Scheme 22 shows a general synthesis of an E-V—C(═O)—P—W—P—R intermediateof the invention wherein, for illustrative purposes, R is a protectinggroup and W is a two aromatic ring unit. Displacement of the α-haloketone 21b proceeds by the addition of an acid under basic conditions(e.g. Et₃N). Bromination of 22b proceeds upon treatment with pyridiniumtribromide, and is followed by the addition of a second acid under basicconditions to provide the diester 22c. Reaction of 22c with an amine oramine salt (e.g. ammonium acetate) affords the imidazole containingmolecule 22d. Oxidation of 22d can be accomplished in the presence ofMnO₂ to provide 22e.

Scheme 23 shows a general synthesis of an E-V—C(═O)—P—W—P—R intermediateof the invention wherein, for illustrative purposes, R is a protectinggroup and W is a two aromatic ring unit. Displacement of the α-haloketone 21d proceeds by the addition of an acid under basic conditions(e.g. Et₃N). Reaction of 23a with an amine or amine salt (e.g. ammoniumacetate) affords the imidazole containing molecule 23b. Oxidation of 23bcan be accomplished in the presence of MnO₂ to provide 23c.

Scheme 24 shows a general synthesis of an R¹—P—W—P—R² intermediate ofthe invention wherein, for illustrative purposes, R¹ and R² areindependent protecting groups and W is a three aromatic ring unitconstructed via a transition metal mediated cross-coupling reaction. Forillustrative purposes, W is constructed from a tetracyclic aromaticring, wherein X¹ and X² are independent halogens or halogen equivalentsthat may be suitably protected. A transition metal-mediatedcross-coupling reaction with butylvinylether, in the presence ofpalladium acetate and dppp, provides the divinyl compound 24a. Treatmentof 24a with N-bromosuccinimide installs the corresponding α-halo ketone.Displacement of the α-halo ketone 24b proceeds by the addition of twoequivalents of acid under basic conditions (e.g. Et₃N). Reaction of 24cwith an amine or amine salt (e.g. ammonium acetate) affords thebis-imidazole containing molecule 24d.

Scheme 25 shows a general synthesis of an E-V—C(═O)—P—W—P—C(═O)—V-Emolecule of the invention wherein, for illustrative purposes, E isethylcarbonylamino. The treatment of either 25a or 25c with one or twoequivalents respectively of propionyl chloride under basic conditions(e.g. sodium hydroxide) provides the molecule 25b or 25d.

In one embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

P^(1a) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected fromhydrogen and alkyl; and where in arylalkyl the alkyl can be substitutedwith up to three aryl groups, and the alkyl part of the arylalkyl isfurther optionally substituted with one or two additional groupsindependently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy,haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group,arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P5), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R, C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R¹⁶ that are independently        selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and        —NR^(Pa)R^(Pb), wherein the alkyl can optionally form a fused        three- to six-membered ring with an adjacent carbon atom,        wherein the three- to six-membered ring is optionally        substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d), (NR^(c)R^(d))alkenyl,(NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl; R^(c) and R^(d) areindependently selected from hydrogen, alkenyloxycarbonyl with one or twogroups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,cycloalkyl, and cycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; and

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁴ is a six membered aromatic or heteroaromatic or five memberedheteroraromatic ring;

X⁵ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁵ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Z⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Z is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —CH₂—O—CH₂—, —S—, —S(O)₂—, —C(O)—,—CF₂—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—; and

Z⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰,P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) and P^(1b) isselected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ andP³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(h)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11).

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

Y¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

X¹⁴ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

each Y¹⁶ is a bicyclic aromatic ring system comprising eight to 12 atomsoptionally including one or more heteroatoms selected from O, S, and N,which bicyclic ring system is optionally with one or more groupsindependently selected from halo, haloalkyl, alkyl and oxo.

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰,P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) and P^(1b) isselected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ andP³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

Y¹⁸ is selected from A⁰, A¹, A², A³, A⁷, A¹⁵, A¹⁶, and A²⁰;

each A⁰ is independently:

wherein:

-   -   each R^(A3) is independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl,        halo, haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b),        (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl; R^(a) and R^(b)        are each independently selected from the group consisting of        hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,        arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        and heterocyclylalkyl; and each    -   bb is independently 0, 1, 2, 3, or 4; or    -   each A⁰ is independently a six-membered heteroaromatic ring        containing one, two, or three nitrogen atoms, which ring is        optionally substituted with 1, 2, 3, or 4 R^(A3) groups;

each A¹ is independently:

wherein:

-   -   each R^(A1) is independently selected from cyano, nitro, SOR⁴,        SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,        cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl,        (heterocycle)alkyl, wherein each alkyl, heterocycle and        cycloalkyl is optionally substituted with one or more halo; and    -   each R⁴ is independently selected from H, alkyl, haloalkyl,        aryl, and arylalkyl;    -   each cc is independently 1, 2, 3, or 4;

each A² is independently:

wherein:

-   -   each R^(A1) is independently selected from cyano, nitro, SOR⁴,        SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,        cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl,        (heterocycle)alkyl, wherein each alkyl, heterocycle and        cycloalkyl is optionally substituted with one or more halo;

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl;

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bband cc is 1, 2, 3, or 4;

each A³ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is substituted with one ormore R^(A1) groups, and which ring is optionally substituted with one ormore R^(A3) groups;

each A⁷ is independently:

wherein:

-   -   each H⁷ is independently a five-membered heteroaromatic ring,        which H⁷ is optionally substituted with one or more groups        independently selected from R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each        R is independently selected from H or alkyl;

each A¹⁵ is independently:

wherein:

-   -   each H¹⁴ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic carbocycle which is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A¹⁶ is independently:

wherein:

-   -   each H¹⁵ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic heterocycle that comprises at        least one heteroatom in the ring system, which ring system is        optionally substituted with one or more groups independently        selected from R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A²⁰ is independently a 5 or 6 membered heteroaryl ring that isoptionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3);

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(—O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(h)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P²⁰ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; and

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

X¹⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

P^(1a) and P^(1b) are each independently selected from P⁰, P¹, P³, P⁵,P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹, and P³⁰;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X²⁰ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

Y²¹ is a bicyclic aromatic ring system comprising eight to 12 atomsoptionally including one or more heteroatoms selected from O, S, and N,which bicyclic ring system is optionally with one or more groupsindependently selected from halo, haloalkyl, alkyl and oxo;

Y²² is selected from A⁰, A¹, A², A³, A⁷, A¹⁵, A¹⁶, and A²⁰;

each A⁰ is independently:

wherein:

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl; and each

bb is independently 0, 1, 2, 3, or 4; or

each A⁰ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is optionally substitutedwith 1, 2, 3, or 4 R^(A3) groups;

each A¹ is independently:

wherein:

each R^(A1) is independently selected from cyano, nitro, SOR⁴, SO₂R⁴,-alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl,(halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl,wherein each alkyl, heterocycle and cycloalkyl is optionally substitutedwith one or more halo; and

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

each cc is independently 1, 2, 3, or 4;

each A² is independently:

wherein:

each R^(A1) is independently selected from cyano, nitro, SOR⁴, SO₂R⁴,-alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl,(halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl,wherein each alkyl, heterocycle and cycloalkyl is optionally substitutedwith one or more halo;

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl;

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bband cc is 1, 2, 3, or 4;

each A³ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is substituted with one ormore R^(A1) groups, and which ring is optionally substituted with one ormore R^(A3) groups;

each A⁷ is independently:

wherein:

each H⁷ is independently a five-membered heteroaromatic ring, which H⁷is optionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3); and

each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O), C(═O)NR,CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each R isindependently selected from H or alkyl;

each A¹⁵ is independently:

wherein:

-   -   each H¹⁴ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic carbocycle which is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A¹⁶ is independently:

wherein:

each H¹⁵ is independently a fused unsaturated, partially unsaturated orsaturated tricyclic heterocycle that comprises at least one heteroatomin the ring system, which ring system is optionally substituted with oneor more groups independently selected from R^(A1) and R^(A3); and

-   -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A²⁰ is independently a 5 or 6 membered heteroaryl ring that isoptionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3);

each L⁹ is independently a fused-tetracyclic saturated, partiallyunsaturated, or aromatic heterocyclic ring system that is optionallysubstituted with one or more groups independently selected from oxo,halo, —R^(L9), —OR^(L9), —SR^(L9), —CF₃, —CCl₃, —OCF₃, —CN, —NO₂,—N(R^(L9))C(═O)R^(L9), —C(═O)R^(L9), —OC(═O)R^(L9), —C(O)OR^(L9),—C(═O)NR^(L9), —S(═O)R^(L9), —S(═O)₂OR^(L9), S(═O)₂R^(L9),—OS(═O)₂OR^(L9), —S(═O)₂NR^(L9), alkoxyalkyl, arylalkoxycarbonyl, halo,haloalkyl, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl;

each R^(L9) is independently —H, alkyl, aryl, arylalkyl, or heterocycle;and

R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

P^(1a) and P^(1b) are each independently selected from P⁰, P¹, P³, P⁵,P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹, and P³⁰;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyloxyalkyloxy,        aryloxyalkyloxy,

heteroaryloxyakyloxy, heterocyclyloxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl,—NR^(hh)R^(h), (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein eachR^(h) is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl,haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo and heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

-   -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1,2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R′ are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and wherein each W^(1a) is substituted with one or more (e.g. 1,2, 3, or 4):

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH—N—;—N═CH—; or —CH═CH—

Y¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

X¹⁴ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P^(0a) and the other of P^(1a)and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

each P^(0a) is independently:

each R^(P5) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

ps is independently 0, 1, 2, 3, or 4;

pn is independently 0, 1, or 2;

po is independently 1, 2, or 3;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h)a)lkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl,

arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring; wherein eachR^(hh) is independently aryl, arylalkyl, heterocycle, heterocyclyoxy,alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,sulfonylalkyl, (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),—C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) areindependently selected from R^(P5), cyano, alkylsulfonyl, arylsulfonyl,(NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl,haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,(NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy,oxo, heterocyclyl; wherein each R^(h) is independently —H, alkyl,alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,sulfonylalkyl; and when two R^(h) groups are present then they may cometogether with the atoms to which they are bound to form a 4-15 memberedheterocyclic ring;

-   -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R, C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is compound of formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P^(0b) and the other of P^(1a)and P^(1b) is selected from P²¹, P³, P⁶, P⁷, P²⁸, P¹², P¹⁵ and P³⁸;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

each P^(0b) is independently:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb)

each R^(P5) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

ps is independently 0, 1, 2, 3, or 4;

pn is independently 0, 1, or 2;

each P²¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, —NR^(hh)R^(h), (NR^(hh)R^(h))carbonyl,        wherein each R^(h) is independently —H, alkyl, alkoxyamino,        aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P²⁸ is independently a ring of the formula:

wherein:

-   -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), where in two        R^(P13) groups are taken together with the carbon to which they        are attached and form a 4-6 membered heterocyclic ring;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1,2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P³⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is a compound of any one of formulae 1-25, 25b, 25c, and 25d asshown in Table 1, or a pharmaceutically acceptable salt or prodrugthereof.

In another embodiment the invention provides a compound of the inventionwhich is a compound of any one of formulae 26-102 as shown in Table 2,or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is a compound of any one of formulae 103-289 as shown in Table 3,or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of the inventionwhich is a compound formula (I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

P^(1a) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected fromhydrogen and alkyl; and where in arylalkyl the alkyl can be substitutedwith up to three aryl groups, and the alkyl part of the arylalkyl isfurther optionally substituted with one or two additional groupsindependently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy,haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group,arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(hh)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P5) that are independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; and where        two groups R^(P15) that are attached to the same carbon when        taken together with the carbon to which they are attached can        form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d), (NR^(c)R^(d))alkenyl,(NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl; R^(c) and R^(d) areindependently selected from hydrogen, alkenyloxycarbonyl with one or twogroups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,cycloalkyl, and cycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; and

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁴ is a six membered aromatic or heteroaromatic or five memberedheteroraromatic ring;

X⁵ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁵ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Z⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Z⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —CH₂—O—CH₂—, —S—, —S(O)₂—, —C(O)—,—CF₂—, —OC(O)—, —(O)CO—, or —CH═CH—;

X⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

Y⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—; and

Z⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S— CH₂—, —CH₂—S—, —OC(O)—, —(O)CO—, or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof;

provided the compound of formula (I) is not:

In one specific embodiment E^(1a) is E⁰.

In one specific embodiment E^(1a) is E¹.

In one specific embodiment E^(1a) is selected from:

In one specific embodiment E^(1a) is —N(H)alkoxycarbonyl.

In one specific embodiment E^(1a) is —N(H)C(═O)OMe.

In one specific embodiment E^(1b) is E⁰.

In one specific embodiment

In one specific embodiment E^(1b) is E¹.

In one specific embodiment E^(1b) is selected from:

In one specific embodiment E^(1b) is —N(H)alkoxycarbonyl.

In one specific embodiment E^(1b) is —N(H)C(═O)OMe.

In one specific embodiment V^(1a) is V⁰.

In one specific embodiment V^(1a) is selected from:

In one specific embodiment V^(1b) is V⁰.

In one specific embodiment V^(1b) is selected from:

In one specific embodiment E^(1a)-V^(1a) taken together are R^(9a).

In one specific embodiment R^(9a) is selected from:

In one specific embodiment E^(1b)-V^(1b) taken together are R^(9b).

In one specific embodiment R^(9b) is selected from:

In one specific embodiment P^(1a) is P⁰.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P¹.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P³.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P⁵.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P⁶.

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1a) is P⁷.

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1a) is P⁸.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P¹⁰.

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1a) is P¹².

In one specific embodiment P^(1a) is P¹⁵.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P¹⁸.

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1b) is P⁰.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P¹.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P³.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P⁵.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P⁶.

In one specific embodiment P^(1b) is:

In one specific embodiment P^(1b) is P⁷.

In one specific embodiment P^(1b) is:

In one specific embodiment P^(1b) is P⁸.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P¹⁰.

In one specific embodiment P^(1b) is:

In one specific embodiment P^(1b) is P¹².

In one specific embodiment P^(1b) is P¹⁵.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1b) is P¹⁸.

In one specific embodiment P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b):

In one specific embodiment at least one of P^(1a) and P^(1b):

In one specific embodiment at least one of P^(1a) and P^(1b):

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1b) is selected from

In one specific embodiment P^(1b) is selected from:

In one specific embodiment W^(1a) is 101, 102, 103, or 104.

In one specific embodiment W^(1a) is 105 or 106.

In one specific embodiment W^(1a) is

In one specific embodiment X¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Y¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is

In one specific embodiment X² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is

In one specific embodiment X³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Y³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is

In one specific embodiment W^(1a) is

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is

In one specific embodiment X⁵ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Y⁵ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment W^(1a) is

In one specific embodiment X⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Y⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment W^(1a) is

In one specific embodiment X⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Y⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Z⁷ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment W^(1a) is

In one specific embodiment X⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Y⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Z⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment W^(1a) is

In one specific embodiment X⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Y⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment Z⁹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—CH₂—O—CH₂—, or —CH═CH—.

In one specific embodiment W^(1a) is optionally substituted with one ormore (e.g. 1, 2, 3, or 4) groups independently selected from halo,alkyl, haloalkyl, cyano, and

In one specific embodiment W^(1a) is 107, 108, or 109.

In one specific embodiment W^(1a) is 103a.

In one specific embodiment W^(1a) is 103b.

In one specific embodiment W^(1a) is 103d.

In one specific embodiment W^(1a) is 103e.

In one specific embodiment W^(1a) is 103i.

In one specific embodiment P^(1a) is

In one specific embodiment P^(1b) is

In one specific embodiment P^(1a) is

In one specific embodiment P^(1b) is

In one specific embodiment W^(1a) is substituted with one or more (e.g.1, 2, 3, or 4) groups independently selected from

In one specific embodiment W^(1a) is substituted with one or more (e.g.1, 2, 3, or 4) fluoro.

In one specific embodiment the invention provides a compound which hasany one of formulae 1-25, 25b, 25c, and 25d as shown in Table 1hereinabove, or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the compound is not a compound of formula:

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment P³⁰ is:

In one specific embodiment the invention provides the compound:

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or Ea-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰,P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) and P^(1b) isselected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ andP³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

Y¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

X¹⁴ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

each Y¹⁶ is a bicyclic aromatic ring system comprising eight to 12 atomsoptionally including one or more heteroatoms selected from O, S, and N,which bicyclic ring system is optionally with one or more groupsindependently selected from halo, haloalkyl, alkyl and oxo.

or a pharmaceutically acceptable salt or prodrug thereof;

provided the compound of formula (I) is not:

In one specific embodiment W^(1a) is formula 116.

In one specific embodiment W^(1a) is:

In one specific embodiment X¹² is: X¹² is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—S—, —O—, —CO—, —CF₂—, or —CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment X¹⁴ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —S—, —O—,—CO—, —CF₂—, or —CH═CH—

In one specific embodiment W^(1a) is:

In one specific embodiment X¹³ is:

X¹³ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —S—, —O—, —CO—, —CF₂—, or —CH═CH—

In one specific embodiment W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹⁶ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

Y¹⁶ is a bicyclic aromatic ring system comprising eight to 12 atomsoptionally including one or more heteroatoms selected from O, S, and N,which bicyclic ring system is optionally with one or more groupsindependently selected from halo, haloalkyl, alkyl and oxo.

In one specific embodiment Y¹⁶ is benzothiophene, quinoline,isoquinoline, and quinazoline.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment X¹⁶ is: X¹⁶ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—S—, —O—, —CO—, —CF₂—, or —CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment X¹⁶ is CH2-CH2, CH2-O, O—CH2-, —S—, —O—,—CO—, —CF2- or CH═CH.

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰,P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) and P^(1b) isselected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ andP³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

Y¹⁸ is selected from A⁰, A¹, A², A³, A⁷, A¹⁵, A¹⁶, and A²⁰;

each A⁰ is independently:

wherein:

-   -   each R^(A3) is independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl,        halo, haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b),        (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl; R^(a) and R^(b)        are each independently selected from the group consisting of        hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,        arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        and heterocyclylalkyl; and each    -   bb is independently 0, 1, 2, 3, or 4; or    -   each A⁰ is independently a six-membered heteroaromatic ring        containing one, two, or three nitrogen atoms, which ring is        optionally substituted with 1, 2, 3, or 4 R^(A3) groups;

each A¹ is independently:

wherein:

-   -   each R^(A1) is independently selected from cyano, nitro, SOR⁴,        SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,        cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl,        (heterocycle)alkyl, wherein each alkyl, heterocycle and        cycloalkyl is optionally substituted with one or more halo; and    -   each R⁴ is independently selected from H, alkyl, haloalkyl,        aryl, and arylalkyl;    -   each cc is independently 1, 2, 3, or 4;

each A² is independently:

wherein:

-   -   each R^(A1) is independently selected from cyano, nitro, SOR⁴,        SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,        cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl,        (heterocycle)alkyl, wherein each alkyl, heterocycle and        cycloalkyl is optionally substituted with one or more halo;

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl;

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bband cc is 1, 2, 3, or 4;

each A³ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is substituted with one ormore R^(A1) groups, and which ring is optionally substituted with one ormore R^(A3) groups;

each A⁷ is independently:

wherein:

-   -   each H⁷ is independently a five-membered heteroaromatic ring,        which H⁷ is optionally substituted with one or more groups        independently selected from R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each        R is independently selected from H or alkyl;

each A¹⁵ is independently:

wherein:

-   -   each H¹⁴ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic carbocycle which is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A¹⁶ is independently:

wherein:

-   -   each H¹⁵ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic heterocycle that comprises at        least one heteroatom in the ring system, which ring system is        optionally substituted with one or more groups independently        selected from R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A²⁰ is independently a 5 or 6 membered heteroaryl ring that isoptionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3);

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═=)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11).

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(h)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P²⁰ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; and

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

X¹⁸ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment W^(1a) is:

In one specific embodiment X¹⁸ is: X¹⁶ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—S—, —O—, —CO—, —CF₂—, or —CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment X¹⁸ is X¹⁶ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—,—S—, —O—, —CO—, —CF₂—, or —CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment X¹⁸ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —S—, —O—,—CO—, —CF₂—, or —CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment X¹⁸ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —S—, —O—,—CO—, —CF₂—, or —CH═CH—.

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

P^(1a) and P^(1b) are each independently selected from P⁰, P¹, P³, P⁵,P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹, and P³⁰;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P11) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps is 2

pn is 0, 1 or 2;

X is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is 0,X is CH₂.

each R^(P13) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P13) that are attached to the same carbon are taken together with thecarbon to which they are attached and form a 4-6 membered heterocyclicring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X²⁰ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

Y²¹ is a bicyclic aromatic ring system comprising eight to 12 atomsoptionally including one or more heteroatoms selected from O, S, and N,which bicyclic ring system is optionally with one or more groupsindependently selected from halo, haloalkyl, alkyl and oxo;

Y²² is selected from A⁰, A¹, A², A³, A⁷, A¹⁵, A¹⁶, and A²⁰;

each A⁰ is independently:

wherein:

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl; and each

bb is independently 0, 1, 2, 3, or 4; or

each A⁰ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is optionally substitutedwith 1, 2, 3, or 4 R^(A3) groups;

each A¹ is independently:

wherein:

each R^(A1) is independently selected from cyano, nitro, SOR⁴, SO₂R⁴,-alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl,(halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl,wherein each alkyl, heterocycle and cycloalkyl is optionally substitutedwith one or more halo; and

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

each cc is independently 1, 2, 3, or 4;

each A² is independently:

wherein:

each R^(A1) is independently selected from cyano, nitro, SOR⁴, SO₂R⁴,-alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴, cycloalkyl,(halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl,wherein each alkyl, heterocycle and cycloalkyl is optionally substitutedwith one or more halo;

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl;

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bband cc is 1, 2, 3, or 4;

each A³ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is substituted with one ormore R^(A1) groups, and which ring is optionally substituted with one ormore R^(A3) groups;

each A⁷ is independently:

wherein:

each H⁷ is independently a five-membered heteroaromatic ring, which H⁷is optionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3); and

each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O), C(═O)NR,CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each R isindependently selected from H or alkyl;

each A¹⁵ is independently:

wherein:

-   -   each H¹⁴ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic carbocycle which is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A¹⁶ is independently:

wherein:

each H¹⁵ is independently a fused unsaturated, partially unsaturated orsaturated tricyclic heterocycle that comprises at least one heteroatomin the ring system, which ring system is optionally substituted with oneor more groups independently selected from R^(A1) and R^(A3); and

-   -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;    -   each A²⁰ is independently a 5 or 6 membered heteroaryl ring that        is optionally substituted with one or more groups independently        selected from R^(A1) and R^(A3);    -   each L⁹ is independently a fused-tetracyclic saturated,        partially unsaturated, or aromatic heterocyclic ring system that        is optionally substituted with one or more groups independently        selected from oxo, halo, —R^(L9), —OR^(L9), —SR^(L9), —CF₃,        —CCl₃, —OCF₃, —CN, —NO₂, —N(R^(L9))C(═O)R^(L9), —C(═O)R^(L9),        —OC(═O)R^(L9), —C(O)OR^(L9), —C(═O)NR^(L9), —S(═O)R^(L9),        —S(═O)₂OR^(L9), —S(═O)₂R^(L9) OS(═O)₂OR^(L9), —S(O)₂NR^(L9),        alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl,        —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl;

each R^(L9) is independently —H, alkyl, aryl, arylalkyl, or heterocycle;and

R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

P¹a and P^(1b) are each independently selected from P⁰, P¹, P³, P⁵, P⁶,P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹, and P³⁰;

each P⁰ is independently:

wherein:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyloxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(h)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each P¹⁹ is:

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

W^(1a) is selected from:

wherein each W^(1a) is optionally substituted with one or more (e.g. 1,2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl,cyano, and wherein each W^(1a) is substituted with one or more (e.g. 1,2, 3, or 4):

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

Y¹¹ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹² is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—

X¹³ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—; and

X¹⁴ is —CH₂—, —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, —CH₂—O—CH₂—, —S—, —S(O)₂—,—C(O)—, —CF₂—, —O—, —S—CH₂—, —CH₂—S—, —O—C(O)—, —C(O)—O—, —CH═N—;—N═CH—; or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment X¹¹ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, or—CH═CH—.

In one specific embodiment Y¹¹ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, or—CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment X¹¹ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, or—CH═CH—.

In one specific embodiment Y¹¹ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, or—CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment X¹¹ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, or—CH═CH—.

In one specific embodiment Y¹¹ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, or—CH═CH—.

In one specific embodiment W^(1a) is:

In one specific embodiment W^(1a) is:

In one specific embodiment R is H, methyl, cyclopropyl, phenyl, or

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P^(0a) and the other of P^(1a)and P^(1b) is selected from P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

each A⁰ is independently:

wherein:

-   -   each R^(A3) is independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl,        halo, haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b),        (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl; R^(a) and R^(b)        are each independently selected from the group consisting of        hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,        arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        and heterocyclylalkyl; and each    -   bb is independently 0, 1, 2, 3, or 4; or    -   each A⁰ is independently a six-membered heteroaromatic ring        containing one, two, or three nitrogen atoms, which ring is        optionally substituted with 1, 2, 3, or 4 R³ groups;

each P^(0a) is independently:

wherein:

each R^(P5) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

ps is independently 0, 1, 2, 3, or 4;

pn is independently 0, 1, or 2;

po is independently 1, 2, or 3;

each P¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h)a)lkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P5), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn is 0, 1, or 2;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps is 2, 3, 4, 5, or 6;    -   pn is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq and ps are independently 0, 1, 2, 3, or 4;    -   pm and pn are independently 0, 1, or 2;    -   po and pp are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

E^(1a) is E⁰ or E¹, or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰ or E¹, or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is selected from P^(0b) and the other of P^(1a)and P^(1b) is selected from P²¹, P³, P⁶, P⁷, P²⁸, P¹², P¹⁵ and P³⁸;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl, aryl,and heterocyclyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl,cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl,alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl,heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl,wherein each R is independently selected from hydrogen and alkyl; andwhere in arylalkyl the alkyl can be substituted with up to three arylgroups, and the alkyl part of the arylalkyl is further optionallysubstituted with one or two additional groups independently selectedfrom alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl,heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), —(NR^(X)R^(Y))alkyl, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can besubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl,arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a secondheterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy,hydroxyalkyl, nitro, —NR^(X)R^(Y), (NR^(X)R^(Y))alkyl, and oxo, whereinthe alkyl part of the arylalkyl and the heterocyclylalkyl areunsubstituted and wherein the aryl, the aryl part of the arylalkyl; thearyl part of the arylcarbonyl, the second heterocyclyl group, and theheterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonylare further optionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

each A⁰ is independently:

wherein:

-   -   each R^(A3) is independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl,        halo, haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b),        (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl; R^(a) and R^(b)        are each independently selected from the group consisting of        hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,        arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        and heterocyclylalkyl; and each    -   bb is independently 0, 1, 2, 3, or 4; or    -   each A⁰ is independently a six-membered heteroaromatic ring        containing one, two, or three nitrogen atoms, which ring is        optionally substituted with 1, 2, 3, or 4 R^(A3) groups;

each P^(0b) is independently:

X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb)

each R^(P5) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

ps is independently 0, 1, 2, 3, or 4;

pn is independently 0, 1, or 2;

each P²¹ is independently:

wherein:

-   -   X is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, —NR^(hh)R^(h), (NR^(hh)R^(h))carbonyl,        wherein each R^(h) is independently —H, alkyl, alkoxyamino,        aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl,

aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; whereineach R^(hh) is independently aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,sulfonylalkyl, (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),—C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) areindependently selected from R^(P5), cyano, alkylsulfonyl, arylsulfonyl,(NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl,haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,(NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy,oxo, heterocyclyl; wherein each R^(h) is independently —H, alkyl,alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,sulfonylalkyl;

-   -   ps is 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps is 0, 1, 2, 3, or 4;    -   pn is 0, 1, or 2;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring that isattached to the remainder of the compound of formula I through oneN-link and through one C-link; wherein the ring is optionallysubstituted with one or more groups independently selected from R^(P6)and R^(P11);

each P²⁸ is independently a ring of the formula:

wherein:

-   -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo,

haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), where in two R^(P13) groups aretaken together with the carbon to which they are attached and form a 4-6membered heterocyclic ring;

-   -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq is independently 0, 1, 2, 3, or 4;    -   pm is independently 0, 1, or 2;    -   pp is independently 1, 2, or 3;    -   ps is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P³⁸ is:

which is optionally substituted with one or two groups independentlyselected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, andcycloalkylalkyl;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, —(NR^(X)R^(Y))alkyl, and —(NR^(X)R^(Y))carbonyl;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof;

provided the compound of formula (I) is not:

In one specific embodiment E^(1a) is E⁰.In one specific embodiment E^(1a) is E¹.In one specific embodiment E^(1a) is selected from:

In one specific embodiment E^(1a) is —N(H)alkoxycarbonyl.

In one specific embodiment E^(1a) is —N(H)C(═O)OMe.

In one specific embodiment E^(1b) is E⁰.

In one specific embodiment E^(1b) is E¹.

In one specific embodiment E^(1b) is selected from:

In one specific embodiment E^(1b) is —N(H)alkoxycarbonyl.

In one specific embodiment E^(1b) is —N(H)C(═O)OMe.

In one specific embodiment V^(1a) is V⁰.

In one specific embodiment V^(1b) is selected from:

In one specific embodiment E^(1a)-V^(1a) taken together are R^(9a).

In one specific embodiment R^(9a) is selected from:

In one specific embodiment E^(1b)-V^(1b) taken together are R^(9a).

In one specific embodiment R^(9a) is selected from:

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a)and P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵,P¹⁸, P¹⁹ and P³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a)and P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁸,P¹⁹ and P³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P⁸, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) andP^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹ and P³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P⁸, P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) andP^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹ and P³⁰

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P⁸, P¹⁵, P¹⁸, P¹⁹ and P³⁰; and the other of P^(1a) andP^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹ and P³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P⁸, P¹⁵, P¹⁸, and P³⁰; and the other of P^(1a) and P^(1b) isselected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ andP³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P⁸, P¹⁵, and P¹⁸; and the other of P^(1a) and P^(1b) isselected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ andP³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P⁷;and the other of P^(1a) and P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶,P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P¹⁸, and P¹⁹; and the other of P^(1a) and P^(1b) is selectedfrom P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁸, and P³⁰; and the other of P^(1a) andP^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹ and P³⁰.

In one specific embodiment one of P^(1a) and P^(1b) is selected from P³,P⁶, P⁷, P¹⁰, and P¹⁸; and the other of P^(1a) and P^(1b) is selectedfrom P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰.

In one specific embodiment P^(1a) is P⁰.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P¹.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P³.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P⁵.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P⁶.

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1a) is P⁷.

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1a) is P⁸.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P¹⁰.

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1a) is P¹².

In one specific embodiment P^(1a) is P¹⁵.

In one specific embodiment P^(1a) is selected from:

In one specific embodiment P^(1a) is P¹⁸.

In one specific embodiment P^(1a) is:

In one specific embodiment P^(1b) is P⁰.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P¹.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P³.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P⁵.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P⁶.

In one specific embodiment P^(1b) is:

In one specific embodiment P^(1b) is P⁷.

In one specific embodiment P^(1b) is:

In one specific embodiment P^(1b) is P⁸.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P¹⁰.

In one specific embodiment P^(1b) is:

In one specific embodiment P^(1b) is P¹².

In one specific embodiment P^(1b) is P¹⁵.

In one specific embodiment P^(1b) is selected from:

In one specific embodiment P^(1b) is P¹⁸.

In one specific embodiment P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b):

In one specific embodiment at least one of P^(1a) and P^(1b):

In one specific embodiment at least one of P^(1a) and P^(1b):

In one specific embodiment P^(1a) is

In one specific embodiment P^(1b) is

In one specific embodiment P^(1a) is

In one specific embodiment P^(1b) is

In one specific embodiment the invention provides compound which is anyone of formulae 26-102 as shown in Table 2, or a pharmaceuticallyacceptable salt or prodrug thereof.

In one specific embodiment the invention provides compound which is anyone of formulae 103-289 as shown in Table 3, or a pharmaceuticallyacceptable salt or prodrug thereof.

In one specific embodiment the invention provides compound which is anyone of formulae 290-539, or a pharmaceutically acceptable salt orprodrug thereof.

In one specific embodiment the invention provides compound which is aprodrug or a pharmaceutically acceptable salt thereof.

In one specific embodiment the invention provides a pharmaceuticalcomposition comprising a compound of the invention and at least onepharmaceutically acceptable carrier.

In one specific embodiment the invention provides for the use of acompound of the invention in treating disorders associated with HCV. Inone specific embodiment the composition can optionally further compriseat least one additional therapeutic agent. In one specific embodimentthe additional therapeutic agent is selected from the group consistingof interferons, ribavirin analogs, NS3 protease inhibitors, NS5bpolymerase inhibitors, alpha-glucosidase 1 inhibitors,hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs fortreating HCV. In one specific embodiment the composition can optionallyfurther comprise a nucleoside analogue. In one specific embodiment thecomposition can optionally further comprise an interferon or pegylatedinterferon. In one specific embodiment the composition the nucleosideanalogue is selected from ribavirin, viramidine, levovirin, aL-nucleoside, and isatoribine and said interferon is α-interferon orpegylated interferon.

In one specific embodiment the invention provides a method of treatingdisorders associated with hepatitis C, said method comprisingadministering to an individual a pharmaceutical composition whichcomprises a therapeutically effective amount of the compound asdescribed in any of claims 1-288 or a pharmaceutically acceptable salt,or prodrug thereof.

In one specific embodiment the invention provides a compound of theinvention for use in medical therapy.

In one specific embodiment the invention provides the use of a compoundof the invention for preparing a medicament for treating hepatitis C ora hepatitis C associated disorder.

In one specific embodiment the invention provides a compound of theinvention for use in the prophylactic or therapeutic treatment ofhepatitis C or a or a hepatitis C associated disorder.

In one specific embodiment the invention provides a novel compound asdescribed herein.

In one specific embodiment the invention provides a novel syntheticmethod as described herein.

Specific Embodiment A

In one specific embodiment the invention provides a compound of formula(I) wherein W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, orheteroaryl;

wherein:

either Y⁵ is absent and Y⁶ is —CH₂—CH₂—, —O—CH₂—, —CH₂—O—, or —CH═CH—;or Y⁶ is absent and Y⁵ is —CH₂—CH₂—, —O—CH₂—, —CH₂—O—, or —CH═CH—; and

X⁵ is —CH₂—CH₂— or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound of formulaI wherein W^(1a) has the formula:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, orheteroaryl;

Y⁶ is —CH₂—CH₂—, —O—CH₂—, —CH₂—O—, or —CH═CH—; and

X⁵ is —CH₂—CH₂— or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound of formula(I) wherein W^(1a) has the formula

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, orheteroaryl;

Y⁵ is —CH₂—CH₂—, —O—CH₂—, —CH₂—O—, or —CH═CH—; and

X⁵ is —CH₂—CH₂— or —CH═CH—;

or a pharmaceutically acceptable salt or prodrug thereof

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) has the formula:

and W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3, or4) groups independently selected from halo, alkyl, haloalkyl, cyano, and

each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, orheteroaryl;

Y⁵ is —O—CH₂—, or —CH₂—O—;

X⁵ is —CH₂—CH₂— or —CH═CH—;

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

P^(1a) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁵, P¹⁸, P¹⁹, andP³⁰;

P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(V02) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X₁ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(h)R^(h))carbonyl-, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P100), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(P100) is independently        selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and        —NR^(P101)R^(P102), wherein the alkyl can optionally form a        fused three- to six-membered ring with an adjacent carbon atom,        wherein the three- to six-membered ring is optionally        substituted with one or two alkyl groups; and R^(P101) and        R^(P102) are each independently H, alkyl, aryl, or arylalkyl; or        R^(P101) and R^(P102) taken together with the atom to which they        are attached form a heterocycle;    -   ps1 is 1,2, 3, or 4;    -   pn1 is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps3 is 0, 1, 2, 3, or 4;    -   pn3 is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn3 is 0, 1, or 2;    -   Z₅ is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z₆ is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn6 is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;    -   each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring        that is attached to the remainder of the compound of formula I        through one N-link and through one C-link; wherein the ring is        optionally substituted with one or more groups independently        selected from R^(P67) and R^(P207); wherein R^(P67) is        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(P205)R^(P206), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; R^(P205)        and R^(P206) are each independently H, alkyl, aryl, or        arylalkyl; or R^(P205) and R^(P206) taken together with the atom        to which they are attached form a heterocycle; and R^(P207) is        independently selected from cyano, alkylsulfonyl, arylsulfonyl,        (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl,        haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,        cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyalkyloxy,        heterocyclyloxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,        cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl,        —NR^(hh)R^(h), (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl-,        wherein each R^(h) is independently —H, alkyl, alkoxyamino,        aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl; and when two R^(h) groups are present then they        may come together with the atoms to which they are bound to form        a 4-15 membered heterocyclic ring; wherein each R^(hh) is        independently aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl, (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl,        —S(═O)₂R^(h), —C(═O)R^(h), —C(═O)NR^(h)R^(h);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps8 is 2, 3, 4, 5, or 6;    -   pn8 is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X₁₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq10 and ps10 are independently 0, 1, 2, 3, or 4;    -   pm10 and pn10 are independently 0, 1, or 2;    -   po10 and pp10 are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq12 is independently 0, 1, 2, 3, or 4;    -   pm12 is independently 0, 1, or 2;    -   pp12 is independently 1, 2, or 3;    -   ps12 is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl-, (NR^(hh)R^(h))carbonyl-, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d), (NR^(c)R^(d))alkenyl,(NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl; R^(c) and R^(d) areindependently selected from hydrogen, alkenyloxycarbonyl with one or twogroups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,cycloalkyl, and cycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps30 is 2

pn30 is 0, 1 or 2;

X₃₀ is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is0, X is CH₂.

each R^(P212) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P212) that are attached to the same carbon are taken together withthe carbon to which they are attached and form a 4-6 memberedheterocyclic ring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound which hasformula:

wherein the imidazole ring shown in formula Ib1, Ib2, Ib3, and Ib4 isoptionally substituted with one or more (e.g. 1, 2, 3, or 4) groupsindependently selected from halo, haloalkyl, and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) has the formula:

and W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3, or4) groups independently selected from halo, alkyl, haloalkyl, cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

Y⁵ is —O—CH₂—, or —CH₂—O—;

X⁵ is —CH₂—CH₂— or —CH═CH—;

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

P^(1a) and P^(1b) are each independently selected from:

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; or apharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(alkoxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)C(═O)OMe.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) iscyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino.

In one specific embodiment E^(1a) and E^(1b) are each independentlyselected from cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino and methoxycarbonylamino.

In one specific embodiment at least one of V^(1a) and V^(1b) is V⁰.

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment V^(1a) and V^(1b) are each independentlyselected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom P⁰ and P¹⁵.

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment one of P^(1a) and P^(1b) is:

and the other of P^(1a) and P^(1b) is:

In one specific embodiment one of P^(1a) and P^(1b) is:

and the other of P^(1a) and P^(1b) is:

In one specific embodiment one of P^(1a) and P^(1b) is P⁰.

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is P⁷.

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is P¹⁵.

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom P⁷ and P¹⁵.

In one specific embodiment at least one of —V^(1a)—C(═O)—P^(1a)- and—P^(1b)—C(═O)—V^(1b)— is:

In one specific embodiment at least one of —V^(1a)—C(═O)—P^(1a)- and—P^(1b)—C(═O)—V^(1b)— is:

In one specific embodiment the invention provides a compound prepared inthe Examples herein that is a compound of specific Embodiment A, or asalt or a prodrug thereof.

In one specific embodiment the invention provides the compound:

or a pharmaceutically acceptable salt or prodrug thereof.

Specific Embodiment B

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) has the formula:

wherein:

X¹¹ is —CH₂—CH₂—, —O—CH₂—, or —CH═CH—

Y¹¹ is —CH═CH—

and W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3, or4) groups independently selected from halo, alkyl, haloalkyl, cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is

and the other of P^(1a) and P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶,P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰.

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X₁ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(h)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(h)R^(h))carbonyl-, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P100), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(P100) is independently        selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and        —NR^(P101)R^(P102), wherein the alkyl can optionally form a        fused three- to six-membered ring with an adjacent carbon atom,        wherein the three- to six-membered ring is optionally        substituted with one or two alkyl groups; and R^(P101) and        R^(P102) are each independently H, alkyl, aryl, or arylalkyl; or        R^(P101) and R^(P102) taken together with the atom to which they        are attached form a heterocycle;    -   ps1 is 1, 2, 3, or 4;    -   pn1 is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps3 is 0, 1, 2, 3, or 4;    -   pn3 is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn3 is 0, 1, or 2;    -   Z₅ is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z₆ is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn6 is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;    -   each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring        that is attached to the remainder of the compound of formula I        through one N-link and through one C-link; wherein the ring is        optionally substituted with one or more groups independently        selected from R^(P67) and R^(P207); wherein R^(P67) is        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(P205)R^(P206), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; R^(P205)        and R^(P206) are each independently H, alkyl, aryl, or        arylalkyl; or R^(P205) and R^(P206) taken together with the atom        to which they are attached form a heterocycle; and R^(P207) is        independently selected from cyano, alkylsulfonyl, arylsulfonyl,        (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl,        haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,        cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyalkyloxy,        heterocyclyloxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,        cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl,        —NR^(hh)R^(h), (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl-,        wherein each R^(h) is independently —H, alkyl, alkoxyamino,        aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl; and when two R^(h) groups are present then they        may come together with the atoms to which they are bound to form        a 4-15 membered heterocyclic ring; wherein each R^(hh) is        independently aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl, (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl,        —S(═O)₂R^(h), —C(═O)R^(h), —C(═O)NR^(h)R^(h);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps8 is 2, 3, 4, 5, or 6;    -   pn8 is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X₁₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq10 and ps10 are independently 0, 1, 2, 3, or 4;    -   pm10 and pn10 are independently 0, 1, or 2;    -   po10 and pp10 are independently 1,2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq12 is independently 0, 1, 2, 3, or 4;    -   pm12 is independently 0, 1, or 2;    -   pp12 is independently 1, 2, or 3;    -   ps12 is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl-, (NR^(hh)R^(h))carbonyl-, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d), (NR^(c)R^(d))alkenyl,(NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl; R^(c) and R^(d) areindependently selected from hydrogen, alkenyloxycarbonyl with one or twogroups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,cycloalkyl, and cycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps30 is 2

pn30 is 0, 1 or 2;

X₃₀ is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is0, X is CH₂.

each R^(P212) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P212) that are attached to the same carbon are taken together withthe carbon to which they are attached and form a 4-6 memberedheterocyclic ring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; or apharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) has the formula:

wherein:

X¹¹ is —CH₂—CH₂—, —O—CH₂—, or —CH═CH—

Y¹¹ is —CH═CH—

and W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3, or4) groups independently selected from halo, alkyl, haloalkyl, cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is

and the other of P^(1a) and P^(1b) is selected:

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; or apharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(alkoxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)C(═O)OMe.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) iscyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino.

In one specific embodiment E^(1a) and E^(1b) are each independentlyselected from cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino and methoxycarbonylamino.

In one specific embodiment at least one of V^(1a) and V^(1b) is V⁰.

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment V^(1a) and V^(1b) are each independentlyselected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is P⁰.

In one specific embodiment one of P^(1a) and P^(1b) is

and the other of P^(1a) and P^(1b) is selected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment the invention provides a compound prepared inthe Examples herein that is a compound of specific Embodiment B, or asalt or a prodrug thereof.

In one specific embodiment the invention provides the compound:

or a pharmaceutically acceptable salt or prodrug thereof.

Specific Embodiment C

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) is:

wherein W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3,or 4) groups independently selected from halo, alkyl, haloalkyl, cyano,and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X¹⁸ is —CH═CH—, —CH₂CH₂—, or —OCH₂—;

Y¹⁸ is selected from A⁰, A¹, A², A³, A⁷, A¹⁵, A¹⁶, and A²⁰;

each A⁰ is independently:

wherein:

-   -   each R^(A3) is independently selected from alkoxy, alkoxyalkyl,        alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl,        halo, haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b),        (NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonyl; R^(a) and R^(b)        are each independently selected from the group consisting of        hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,        arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,        and heterocyclylalkyl; and each    -   bb is independently 0, 1, 2, 3, or 4; or    -   each A⁰ is independently a six-membered heteroaromatic ring        containing one, two, or three nitrogen atoms, which ring is        optionally substituted with 1, 2, 3, or 4 R^(A3) groups;

each A¹ is independently:

wherein:

-   -   each R^(A1) is independently selected from cyano, nitro, SOR⁴,        SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,        cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl,        (heterocycle)alkyl, wherein each alkyl, heterocycle and        cycloalkyl is optionally substituted with one or more halo; and    -   each R⁴ is independently selected from H, alkyl, haloalkyl,        aryl, and arylalkyl;    -   each cc is independently 1, 2, 3, or 4;

each A² is independently:

wherein:

-   -   each R^(A1) is independently selected from cyano, nitro, SOR⁴,        SO₂R⁴, -alkylSO₂R⁴, haloalkoxy, cyanoalkyl, NR⁴SO₂R⁴,        cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl,        (heterocycle)alkyl, wherein each alkyl, heterocycle and        cycloalkyl is optionally substituted with one or more halo;

each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl;

each R⁴ is independently selected from H, alkyl, haloalkyl, aryl, andarylalkyl;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl,arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl;

each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bband cc is 1, 2, 3, or 4;

each A³ is independently a six-membered heteroaromatic ring containingone, two, or three nitrogen atoms, which ring is substituted with one ormore R^(A1) groups, and which ring is optionally substituted with one ormore R^(A3) groups;

each A⁷ is independently:

wherein:

-   -   each H⁷ is independently a five-membered heteroaromatic ring,        which H⁷ is optionally substituted with one or more groups        independently selected from R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each        R is independently selected from H or alkyl;

each A¹⁵ is independently:

wherein:

-   -   each H¹⁴ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic carbocycle which is        optionally substituted with one or more groups independently        selected from oxo, R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A¹⁶ is independently:

wherein:

-   -   each H¹⁵ is independently a fused unsaturated, partially        unsaturated or saturated tricyclic heterocycle that comprises at        least one heteroatom in the ring system, which ring system is        optionally substituted with one or more groups independently        selected from R^(A1) and R^(A3); and    -   each X^(A) is independently O, NR, SO, SO₂, C(═O), NRC(═O),        C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each        R is independently selected from H or alkyl;

each A²⁰ is independently a 5 or 6 membered heteroaryl ring that isoptionally substituted with one or more groups independently selectedfrom R^(A1) and R^(A3);

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is

and the other of P^(1a) and P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶,P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P5), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X₁ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(hh)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl-, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P100), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(P100) is independently        selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and        —NR^(P101)R^(P102), wherein the alkyl can optionally form a        fused three- to six-membered ring with an adjacent carbon atom,        wherein the three- to six-membered ring is optionally        substituted with one or two alkyl groups; and R^(P101) and        R^(P102) are each independently H, alkyl, aryl, or arylalkyl; or        R^(P101) and R^(P102) taken together with the atom to which they        are attached form a heterocycle;    -   ps1 is 1, 2, 3, or 4;    -   pn1 is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps3 is 0, 1, 2, 3, or 4;    -   pn3 is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P15) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn3 is 0, 1, or 2;    -   Z₅ is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z₆ is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn6 is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;    -   each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring        that is attached to the remainder of the compound of formula I        through one N-link and through one C-link; wherein the ring is        optionally substituted with one or more groups independently        selected from R^(P67) and R^(P207); wherein R^(P67) is        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(P205)R^(P206), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; R^(P205)        and R^(P206) are each independently H, alkyl, aryl, or        arylalkyl; or R^(P205) and R^(P206) taken together with the atom        to which they are attached form a heterocycle; and R^(P207) is        independently selected from cyano, alkylsulfonyl, arylsulfonyl,        (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl,        haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,        cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyalkyloxy,        heterocyclyloxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,        cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl,        —NR^(hh)R^(h), (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl-,        wherein each R^(h) is independently —H, alkyl, alkoxyamino,        aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl; and when two R^(h) groups are present then they        may come together with the atoms to which they are bound to form        a 4-15 membered heterocyclic ring; wherein each R^(hh) is        independently aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl, (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl,        —S(═O)₂R^(h), —C(═O)R^(h), —C(═O)NR^(h)R^(h);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps8 is 2, 3, 4, 5, or 6;    -   pn8 is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X₁₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq10 and ps10 are independently 0, 1, 2, 3, or 4;    -   pm10 and pn10 are independently 0, 1, or 2;    -   po10 and pp10 are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq12 is independently 0, 1, 2, 3, or 4;    -   pm12 is independently 0, 1, or 2;    -   pp12 is independently 1, 2, or 3;    -   ps12 is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl-, (NR^(hh)R^(h))carbonyl-, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d), (NR^(c)R^(d))alkenyl,(NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl; R^(c) and R^(d) areindependently selected from hydrogen, alkenyloxycarbonyl with one or twogroups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,cycloalkyl, and cycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps30 is 2;

pn30 is 0, 1 or 2;

X₃₀ is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is0, X is CH₂.

each R^(P212) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P212) that are attached to the same carbon are taken together withthe carbon to which they are attached and form a 4-6 memberedheterocyclic ring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; or apharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment X¹⁸ is —CH═CH—.

In one specific embodiment X¹⁸ is —CH₂CH₂—.

In one specific embodiment X¹⁸ is —OCH₂—.

In one specific embodiment Y¹⁸ is selected from A⁰ and A¹.

In one specific embodiment Y¹⁸ is selected from A⁰.

In one specific embodiment Y¹⁸:

wherein each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, hydroxyalkyl, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonyl; R^(a) and R^(b) are each independently selectedfrom the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl; and bb is independently 0, 1, 2, 3,or 4.

In one specific embodiment Y¹⁸:

wherein each R^(A3) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo,haloalkyl, hydroxy, and hydroxyalkyl; and bb is independently 0, 1, 2,3, or 4.

In one specific embodiment Y¹⁸ is phenyl.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(alkoxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)C(═O)OMe.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) iscyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino.

In one specific embodiment E^(1a) and E^(1b) are each independentlyselected from cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino and methoxycarbonylamino.

In one specific embodiment at least one of V^(1a) and V^(1b) is V⁰.

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment V^(1a) and V^(1b) are each independentlyselected from:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is P⁰.

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment the invention provides a compound prepared inthe Examples herein that is a compound of specific Embodiment C, or asalt or a prodrug thereof.

Specific Embodiment D

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) has the formula:

and W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3, or4) groups independently selected from halo, alkyl, haloalkyl, cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is

and the other of P^(1a) and P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶,P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸, P¹⁹ and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P8), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pz), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X₁ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(h)R^(h))carbonyl-, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P100), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(P100) is independently        selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and        —NR^(P101)R^(P102), wherein the alkyl can optionally form a        fused three- to six-membered ring with an adjacent carbon atom,        wherein the three- to six-membered ring is optionally        substituted with one or two alkyl groups; and R^(P101) and        R^(P102) are each independently H, alkyl, aryl, or arylalkyl; or        R^(P101) and R^(P102) taken together with the atom to which they        are attached form a heterocycle;    -   ps1 is 1, 2, 3, or 4;    -   pn1 is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps3 is 0, 1, 2, 3, or 4;    -   pn3 is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups        R^(P15) that are independently selected from alkoxy, alkyl,        aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the        alkyl can optionally form a fused three- to six-membered ring        with an adjacent carbon atom, wherein the three- to six-membered        ring is optionally substituted with one or two alkyl groups; and        where two groups R^(P11) that are attached to the same carbon        when taken together with the carbon to which they are attached        can form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn3 is 0, 1, or 2;    -   Z₅ is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z₆ is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn6 is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;    -   each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring        that is attached to the remainder of the compound of formula I        through one N-link and through one C-link; wherein the ring is        optionally substituted with one or more groups independently        selected from R^(P67) and R^(P207); wherein R^(P67) is        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(P205)R^(P206), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; R^(P205)        and R^(P206) are each independently H, alkyl, aryl, or        arylalkyl; or R^(P205) and R^(P206) taken together with the atom        to which they are attached form a heterocycle; and R^(P207) is        independently selected from cyano, alkylsulfonyl, arylsulfonyl,        (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl,        haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,        cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyalkyloxy,        heterocyclyloxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,        cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl,        —NR^(hh)R^(h), (NR^(h)R^(h))alkyl, (NR^(hh)R^(h))carbonyl-,        wherein each R^(h) is independently —H, alkyl, alkoxyamino,        aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl; and when two R^(h) groups are present then they        may come together with the atoms to which they are bound to form        a 4-15 membered heterocyclic ring; wherein each R^(hh) is        independently aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl, (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl,        —S(═O)₂R^(h), —C(═O)R^(h), —C(═O)NR^(h)R^(h);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps8 is 2, 3, 4, 5, or 6;    -   pn8 is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X₁₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq10 and ps10 are independently 0, 1,2, 3, or 4;    -   pm10 and pn10 are independently 0, 1, or 2;    -   po10 and pp10 are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq12 is independently 0, 1, 2, 3, or 4;    -   pm12 is independently 0, 1, or 2;    -   pp12 is independently 1, 2, or 3;    -   ps12 is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl-, (NR^(hh)R^(h))carbonyl-, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═-O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d), (NR^(c)R^(d))alkenyl,(NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl; R^(c) and R^(d) areindependently selected from hydrogen, alkenyloxycarbonyl with one or twogroups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,cycloalkyl, and cycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps30 is 2;

pn30 is 0, 1 or 2;

X₃₀ is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is0, X is CH₂.

each R^(P212) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P212) that are attached to the same carbon are taken together withthe carbon to which they are attached and form a 4-6 memberedheterocyclic ring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) has the formula:

and W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3, or4) groups independently selected from halo, alkyl, haloalkyl, cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

one of P^(1a) and P^(1b) is

and the other of P^(1a) and P^(1b) P^(1a) is selected from:

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl; and

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(alkoxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)C(═O)OMe.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) iscyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino.

In one specific embodiment E^(1a) and E^(1b) are each independentlyselected from cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino and methoxycarbonylamino.

In one specific embodiment at least one of V^(1a) and V^(1b) is V⁰.

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment V^(1a) and V^(1b) are each independentlyselected from:

In one specific embodiment one of P^(1a) and P^(1b) is

and the other of P^(1a) and P^(1b) P^(1a) is selected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is P⁰.

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment E^(1a)-V^(1a) taken together are R^(9a) orE^(1b)-V^(1b) taken together are R^(9b); wherein R^(9a) or R^(9b) isselected from:

In one specific embodiment the invention provides a compound prepared inthe Examples herein that is a compound of specific Embodiment D, or asalt or a prodrug thereof.

Specific Embodiment E

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) has the formula:

X³ is —CH₂—CH₂—, —CH₂—O—, or —O—CH₂—;

Y³ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, or —CH═CH—.

and W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3, or4) groups independently selected from halo, alkyl, haloalkyl, cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

Y⁵ is —O—CH₂—, or —CH₂—O—;

X⁵ is —CH₂—CH₂— or —CH═CH—;

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

P^(1a) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

P^(1b) is selected from P⁰, P¹, P³, P⁵, P⁶, P⁷, P⁸, P¹⁰, P¹², P¹⁵, P¹⁸,P¹⁹, and P³⁰;

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

each P⁰ is independently:

wherein:

X₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and C(R^(P10))₂;provided that when pn or pm is 0, X is selected from CH₂, CHR^(P10), andC(R^(P10))₂;

each R^(P10) is independently selected from alkoxy, alkyl, aryl, halo,haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can optionallyform a fused three- to six-membered ring with an adjacent carbon atom,wherein the three- to six-membered ring is optionally substituted withone or two alkyl groups;

each R^(P5) and R^(P6) is independently selected from alkoxy, alkyl,aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkylcan optionally form a fused three- to six-membered ring with an adjacentcarbon atom, wherein the three- to six-membered ring is optionallysubstituted with one or two alkyl groups;

R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or arylalkyl;or R^(Pa) and R^(Pb) taken together with the atom to which they areattached form a heterocycle;

pq and ps are independently 0, 1, 2, 3, or 4;

pm and pn are independently 0, 1, or 2;

po and pp are independently 1, 2, or 3;

R^(P7) and R^(P8) are each independently selected from hydrogen,alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR^(Pa)R^(Pb))alkyl; orR^(P7) and R^(P5), together with the carbon atom to which they areattached, form a five or six membered saturated ring optionallycontaining one or two heteroatoms selected from NR^(Pa), O, and S;wherein R^(Pz) is selected from hydrogen and alkyl;

R^(P9) is selected from hydrogen and alkyl;

each P¹ is independently:

wherein:

-   -   X₁ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn is 0, X is selected from CH₂,        CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   at least one R^(P11) is independently selected from cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),        (NR^(hh)R^(h))alkyl, (NR^(hh)R^(h))carbonyl-, wherein each R^(h)        is independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(hh) is independently aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h),        —C(═O)R^(h), —C(═O)NR^(h)R^(h); and the remaining R^(P11) are        independently selected from R^(P100), cyano, alkylsulfonyl,        arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,        heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,        haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,        heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo and heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring; wherein each R^(P100) is independently        selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and        —NR^(P101)R^(P102), wherein the alkyl can optionally form a        fused three- to six-membered ring with an adjacent carbon atom,        wherein the three- to six-membered ring is optionally        substituted with one or two alkyl groups; and R^(P101) and        R^(P102) are each independently H, alkyl, aryl, or arylalkyl; or        R^(P101) and R^(P102) taken together with the atom to which they        are attached form a heterocycle;    -   ps1 is 1, 2, 3, or 4;    -   pn1 is 0, 1, or 2;

each P³ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo group;    -   each R^(P13) is independently selected from R^(P5), cyano,        alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,        heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy,        alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy,        aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy,        (NR^(h)R^(h))alkyloxy, cyanoalkoxy, cyanocycloalkyloxy,        cycloalkyloxy, oxo, heterocyclyl; wherein each R^(h) is        independently —H, alkyl, alkoxyamino, aryl, arylalkyl,        heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,        alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,        alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two        R^(h) groups are present then they may come together with the        atoms to which they are bound to form a 4-15 membered        heterocyclic ring;    -   ps3 is 0, 1, 2, 3, or 4;    -   pn3 is 0, 1, or 2;

each P⁵ is independently a ring of the formula:

wherein:

-   -   the ring is optionally substituted with one or more groups R¹⁵        that are independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; and where        two groups R^(P15) that are attached to the same carbon when        taken together with the carbon to which they are attached can        form a 3-6 membered carbocyclic or heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pn3 is 0, 1, or 2;    -   Z₅ is O, S, S(═O), S(═O)₂, or NR^(f);    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;

each P⁶ is independently a ring of the formula:

wherein:

-   -   the ring is substituted with one or more oxo and is optionally        substituted with one or more groups R^(P16) that are        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl can        optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   Z₆ is O, S, S(═O), S(═O)₂, or NR^(f);    -   pn6 is 0, 1, or 2;    -   each R^(f) is independently —H, alkyl, alkoxyamino, aryl,        arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy,        alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,        —S(═O)₂NR^(h)R^(h), —S(═O)₂R^(h), C(═O)R^(h), C(═O)OR^(h),        —C(═O)NR^(h)R^(h); each R^(h) is independently —H, alkyl,        alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,        cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,        dialkylaminoalkyl, sulfonylalkyl; or when two R^(h) groups are        present then they may come together with the atoms to which they        are bound to form a 4-15 membered heterocyclic ring;    -   each P⁷ is a bridged 5-15 membered bicyclic heterocyclic ring        that is attached to the remainder of the compound of formula I        through one N-link and through one C-link; wherein the ring is        optionally substituted with one or more groups independently        selected from R^(P67) and R^(P207); wherein R^(P67) is        independently selected from alkoxy, alkyl, aryl, halo,        haloalkyl, hydroxy, and —NR^(P205)R^(P206), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; R^(P205)        and R^(P206) are each independently H, alkyl, aryl, or        arylalkyl; or R^(P205) and R^(P206) taken together with the atom        to which they are attached form a heterocycle; and R^(P207) is        independently selected from cyano, alkylsulfonyl, arylsulfonyl,        (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl,        haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,        cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyalkyloxy,        heterocyclyloxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,        cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl,        —NR^(hh)R^(h), (NR^(h)R^(h))alkyl, (NR^(h)R^(h))carbonyl-,        wherein each R^(h) is independently —H, alkyl, alkoxyamino,        aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl; and when two R^(h) groups are present then they        may come together with the atoms to which they are bound to form        a 4-15 membered heterocyclic ring; wherein each R^(hh) is        independently aryl, arylalkyl, heterocycle, heterocyclyoxy,        alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl,        haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,        sulfonylalkyl, (NR^(h)R^(h))sulfonyl, heteroarylsulfonyl,        —S(═O)₂R^(h), —C(═O)R^(h), —C(═O)NR^(h)R^(h);

each P⁸ is independently a ring of the formula:

wherein:

-   -   ps8 is 2, 3, 4, 5, or 6;    -   pn8 is 0, 1 or 2;    -   each R^(P13) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups; where in at        least one case two groups R^(P13) that are attached to the same        carbon are taken together with the carbon to which they are        attached and form a 4-6 membered heterocyclic ring;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;

each P¹⁰ is independently:

wherein:

-   -   X₁₀ is selected from O, S, S(O), SO₂, CH₂, CHR^(P10), and        C(R^(P10))₂; provided that when pn or pm is 0, X is selected        from CH₂, CHR^(P10), and C(R^(P10))₂;    -   each R^(P10) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   each R^(P5) and R^(P6) is independently selected from alkoxy,        alkyl, aryl, halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb),        wherein the alkyl can optionally form a fused three- to        six-membered ring with an adjacent carbon atom, wherein the        three- to six-membered ring is optionally substituted with one        or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq10 and ps10 are independently 0, 1, 2, 3, or 4;    -   pm10 and pn10 are independently 0, 1, or 2;    -   po10 and pp10 are independently 1, 2, or 3;

each P¹² is independently:

wherein:

-   -   each R^(P6) is independently selected from alkoxy, alkyl, aryl,        halo, haloalkyl, hydroxy, and —NR^(Pa)R^(Pb), wherein the alkyl        can optionally form a fused three- to six-membered ring with an        adjacent carbon atom, wherein the three- to six-membered ring is        optionally substituted with one or two alkyl groups;    -   R^(Pa) and R^(Pb) are each independently H, alkyl, aryl, or        arylalkyl; or R^(Pa) and R^(Pb) taken together with the atom to        which they are attached form a heterocycle;    -   pq12 is independently 0, 1, 2, 3, or 4;    -   pm12 is independently 0, 1, or 2;    -   pp12 is independently 1, 2, or 3;    -   ps12 is 1, 2, 3, or 4;

R^(P11) is independently selected from cyano, alkylsulfonyl,arylsulfonyl, (NR^(h)R^(h))sulfonyl, heterocyclylsulfonyl,heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy,cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy,heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy, cyanoalkoxy,cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR^(hh)R^(h),(NR^(hh)R^(h))alkyl-, (NR^(h)R^(h))carbonyl-, wherein each R^(h) isindependently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle,heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl,cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, sulfonylalkyl; and when two R^(h) groups are presentthen they may come together with the atoms to which they are bound toform a 4-15 membered heterocyclic ring; wherein each R^(hh) isindependently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy,alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl,(NR^(h)R^(h))sulfonyl, heteroarylsulfonyl, —S(═O)₂R^(h), —C(═O)R^(h),—C(═O)NR^(h)R^(h); and the remaining R^(P11) are independently selectedfrom R^(P5), cyano, alkylsulfonyl, arylsulfonyl, (NR^(h)R^(h))sulfonyl,heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy,haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy,heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR^(h)R^(h))alkyloxy,cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl;wherein each R^(h) is independently —H, alkyl, alkoxyamino, aryl,arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl,alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R^(h)groups are present then they may come together with the atoms to whichthey are bound to form a 4-15 membered heterocyclic ring;

each P¹⁵ is:

which is substituted with one or two groups independently selected fromalkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl,cyanoalkyl, and cycloalkylalkyl;

each P¹⁸ is:

which is optionally substituted, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d), (NR^(c)R^(d))alkenyl,(NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl; R^(c) and R^(d) areindependently selected from hydrogen, alkenyloxycarbonyl with one or twogroups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl,cycloalkyl, and cycloalkylalkyl;

each P¹⁹ is:

each P³⁰ is independently a ring of the formula:

ps30 is 2;

pn30 is 0, 1 or 2;

X₃₀ is selected from O, S, S(O), SO₂, or CH₂; provided that when pn is0, X is CH₂.

each R^(P212) is independently selected from alkyl-, alkoxyalkyl-,hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-,alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groupsR^(P212) that are attached to the same carbon are taken together withthe carbon to which they are attached and form a 4-6 memberedheterocyclic ring;

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment W^(1a) is:

wherein any imidazole ring shown in W^(1a) is optionally substitutedwith one or more (e.g. 1, 2, 3, or 4) groups independently selected fromhalo, haloalkyl, and alkyl.

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) has the formula:

and W^(1a) is optionally substituted with one or more (e.g. 1, 2, 3, or4) groups independently selected from halo, alkyl, haloalkyl, cyano, and

wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl,or heteroaryl;

X³ is —CH₂—CH₂—, —CH₂—O—, or —O—CH₂—;

Y³ is —CH₂—CH₂—, —CH₂—O—, —O—CH₂—, or —CH═CH—;

E^(1a) is E⁰, E¹, or E², or E^(1a)-V^(1a) taken together are R^(9a);

E^(1b) is E⁰, E¹, or E², or E^(1b)-V^(1b) taken together are R^(9b);

V^(1a) is V⁰ or E^(1a)-V^(1a) taken together are R^(9a);

V^(1b) is V⁰ or E^(1b)-V^(1b) taken together are R^(9b);

each E⁰ is independently —NR^(Ec)R^(Ed) wherein R^(Ec) and R^(Ed) areeach independently selected from hydrogen, alkenyloxycarbonyl,alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl,arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl,cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl,heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro;

each E¹ is independently selected from hydrogen, hydroxy, alkyl,haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;

each E² is independently —NHR^(Ef) wherein R^(Ef) is cycloalkylcarbonylor cycloalkyloxycarbonyl;

each V⁰ is independently alkyl, arylalkyl, alkenyl, CO,(cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl,alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl,carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl,hydroxyalkyl, NR^(VO1)R^(VO1)COalkyl, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and where in arylalkylthe alkyl can be substituted with up to three aryl groups, and the alkylpart of the arylalkyl is further optionally substituted with one or twoadditional groups independently selected from alkoxy, alkylcarbonyloxy,halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl partcan be substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR^(X)R^(Y),(NR^(X)R^(Y))alkyl-, oxo, and —P(O)(OR^(VO2))₂, wherein each R^(VO1) isindependently selected from hydrogen and alkyl; and wherein the alkylpart of the arylalkyl and the heterocyclylalkyl are unsubstituted andwherein the second aryl group, the aryl part of the arylalkyl, the arylpart of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part ofthe heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2,3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(X)R^(Y), (NR^(X)R^(Y))alkyl-, and oxo, wherein the alkyl part ofthe arylalkyl and the heterocyclylalkyl are unsubstituted and whereinthe aryl, the aryl part of the arylalkyl; the aryl part of thearylcarbonyl, the second heterocyclyl group, and the heterocyclyl partof the heterocyclylalkyl and the heterocyclylcarbonyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, and nitro;

P^(1a) and P^(1b) are each independently selected from:

each R^(9a) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

each R^(9b) is independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl,arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl,(cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl,heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy,heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkenyl, (NR^(c)R^(d))alkyl, and (NR^(c)R^(d))carbonyl;R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl,heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl,heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl-,(NR^(e)R^(f))alkylcarbonyl-, (NR^(e)R^(f))carbonyl-,(NR^(e)R^(f))sulfonyl-, —C(NCN)OR′, and —C(NCN)NR^(X)R^(Y), wherein R′is selected from alkyl and unsubstituted phenyl, and wherein the alkylpart of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, andthe heterocyclylalkylcarbonyl are further optionally substituted withone —NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro; R^(e) and R^(f) areindependently selected from hydrogen, alkyl, unsubstituted aryl,unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted(cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstitutedheterocyclylalkyl, (NR^(X)R^(Y))alkyl-, and (NR^(X)R^(Y))carbonyl-;R^(X) and R^(Y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(X′)R^(Y′))carbonyl-, wherein R^(X′)and R^(Y′) are independently selected from hydrogen and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(alkoxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)C(═O)OMe.

In one specific embodiment at least one of E^(1a) and E^(1b) is—N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl).

In one specific embodiment at least one of E^(1a) and E^(1b) iscyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino.

In one specific embodiment E^(1a) and E^(1b) are each independentlyselected from cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino and methoxycarbonylamino.

In one specific embodiment at least one of V^(1a) and V^(1b) is V⁰.

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment at least one of V^(1a) and V^(1b) is selectedfrom:

In one specific embodiment V^(1a) and V^(1b) are each independentlyselected from:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom P⁰ and P¹⁵.

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom:

In one specific embodiment P^(1a) and P^(1b) are each independentlyselected from:

In one specific embodiment one of P^(1a) and P^(1b) is:

and the other of P^(1a) and P^(1b) is:

In one specific embodiment one of P^(1a) and P^(1b) is:

and the other of P^(1a) and P^(1b) is:

In one specific embodiment one of P^(1a) and P^(1b) is P⁰.

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is P⁷.

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is P¹⁵.

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is:

In one specific embodiment at least one of P^(1a) and P^(1b) is selectedfrom P⁷ and P¹⁵.

In one specific embodiment at least one of —V^(1a)—C(═O)—P^(1a)- and—P^(1b)—C(═O)—V^(1b)— is:

at least one of —V^(1a)—C(═O)—P^(1a)- and —P^(1b)—C(═O)—V^(1b)— is:

In one specific embodiment at least one of —V^(1a)—C(═O)—P^(1a)- and—P^(1b)—C(═O)—V^(1b)— is:

Other Specific Embodiments

In one specific embodiment the invention provides a compound of formula(I):

E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)

wherein:

W^(1a) is selected from A, B, C, D, and E:

and W^(1a) is optionally substituted with one or more groupsindependently selected from halo, alkyl, haloalkyl, and cyano;

Y⁵ is —O—CH₂—, or —CH₂—O—; X⁵ is —CH₂—CH₂— or —CH═CH—;

X¹¹ is —CH₂—CH₂—, —O—CH₂—, or —CH═CH—;

X¹⁸ is —CH═CH—, —CH₂CH₂—, or —OCH₂—;

X³ is —CH₂—CH₂—, —CH₂—O—, or —O—CH₂—; Y³ is —CH₂—CH₂—, —CH₂—O—, or—CH═CH—;

E^(1a) is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl) or—N(H)(cycloalkyloxycarbonyl); or E^(1a)-V^(1a) taken together areR^(9a);

E^(1b) is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl) or—N(H)(cycloalkyloxycarbonyl); or E^(1b)-V^(1b) taken together areR^(9b);

V^(1a) and V^(1b) are each independently selected from:

when W^(1a) is selected from A and E, then P^(1a) and P^(1b) are eachindependently selected from:

when W^(1a) is selected from B, C, and D then one of P^(1a) and P^(1b)is

and the other of P^(1a) and P^(1b) P^(1a) is selected from:

R^(9a) and R^(9b) are each independently:

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound whereinW^(1a) has the formula:

and W^(1a) is optionally substituted with one or more groupsindependently selected from halo, alkyl, haloalkyl, and cyano.

In one specific embodiment the invention provides a compound whereinW^(1a) has the formula:

and W^(1a) is optionally substituted with one or more groupsindependently selected from halo, alkyl, haloalkyl, and cyano;

In one specific embodiment the invention provides a compound whereinW^(1a) has the formula:

and W^(1a) is optionally substituted with one or more groupsindependently selected from halo, alkyl, haloalkyl, and cyano.

In one specific embodiment the invention provides a compound whereinW^(1a) has the formula:

and W^(1a) is optionally substituted with one or more groupsindependently selected from halo, alkyl, haloalkyl, and cyano.

In one specific embodiment the invention provides a compound whereinW^(1a) has the formula:

and W^(1a) is optionally substituted with one or more groupsindependently selected from halo, alkyl, haloalkyl, and cyano.

In one specific embodiment the invention provides a compound which hasformula:

wherein the imidazole ring shown in formula A1, A2, A3, and A4 isoptionally substituted with one or more groups independently selectedfrom halo, haloalkyl, cyano, and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound which hasformula:

wherein the imidazole ring shown in formula Ib1 and Ib3 is optionallysubstituted with one or more groups independently selected from halo,haloalkyl, cyano, and alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound wherein X¹⁸is —CH═CH—.

In one specific embodiment the invention provides a compound wherein X¹⁸is —CH₂CH₂—.

In one specific embodiment the invention provides a compound wherein X¹⁸is —OCH₂—.

In one specific embodiment the invention provides a compound whereinW^(1a) is:

wherein any imidazole ring shown in W^(1a) is optionally substitutedwith one or more groups independently selected from halo, haloalkyl,cyano, and alkyl.

In one specific embodiment the invention provides a compound wherein atleast one of E^(1a) and E^(1b) is —N(H)(alkoxycarbonyl).

In one specific embodiment the invention provides a compound wherein atleast one of E^(1a) and E^(1b) is —N(H)C(═O)OMe.

In one specific embodiment the invention provides a compound whereinboth of E^(1a) and E^(1b) are —N(H)C(═O)OMe.

In one specific embodiment the invention provides a compound wherein atleast one of E^(1a) and E^(1b) is —N(H)(cycloalkylcarbonyl) or—N(H)(cycloalkyloxycarbonyl).

In one specific embodiment the invention provides a compound wherein atleast one of E^(1a) and E^(1b) is cyclopropylcarbonylamino,cyclobutylcarbonylamino, cyclopropyloxycarbonylamino orcyclobutyloxycarbonylamino.

In one specific embodiment the invention provides a compound whereinE^(1a) and E^(1b) are each independently selected fromcyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopropyloxycarbonylamino and methoxycarbonylamino.

In one specific embodiment the invention provides a compound wherein atleast one of V^(1a) and V^(1b) is selected from:

In one specific embodiment the invention provides a compound wherein atleast one of V^(1a) and V^(1b) is:

In one specific embodiment the invention provides a compound wherein atleast one of V^(1a) and V^(1b) is selected from:

In one specific embodiment the invention provides a compound whereinV^(1a) and V^(1b) are each independently selected from:

In one specific embodiment the invention provides a compound whereinR^(9a) or R^(9b) is selected from:

In one specific embodiment the invention provides a compound wherein atleast one of P^(1a) and P^(1b) is selected from:

In one specific embodiment the invention provides a compound whereinP^(1a) and P^(1b) are each independently selected from:

In one specific embodiment the invention provides a compound wherein atleast one of P^(1a) and P^(1b) is selected from:

In one specific embodiment the invention provides a compound whereinP^(1a) and P^(1b) are each independently selected from:

In one specific embodiment the invention provides a compound wherein oneof P^(1a) and P^(1b) is:

and the other of P^(1a) and P^(1b) is:

In one specific embodiment the invention provides a compound wherein oneof P^(1a) and P^(1b) is:

and the other of P^(1a) and P^(1b) is:

In one specific embodiment the invention provides a compound wherein atleast one of P^(1a) and P^(1b) is:

In one specific embodiment the invention provides a compound wherein atleast one of P^(1a) and P^(1b) is:

In one specific embodiment the invention provides a compound wherein atleast one of P^(1a) and P^(1b) is:

In one specific embodiment the invention provides a compound wherein atleast one of P^(1a) and P^(1b) is:

In one specific embodiment the invention provides a compound wherein atleast one of P^(1a) and P^(1b) is:

In one specific embodiment the invention provides a compound wherein atleast one of P^(1a) and P^(1b) is:

In one specific embodiment the invention provides a compound wherein atleast one of —V^(1a)—C(═O)—P^(1a)- and —P^(1b)—C(═)—V^(1b)— is:

In one specific embodiment the invention provides a compound wherein atleast one of —V^(1a)—C(═O)—P^(1a)- and —P^(1b)—C(═O)—V^(1b)— is:

In one specific embodiment the invention provides a compound whereinboth of —V^(1a)—C(═O)—P^(1a)- and —P^(1b)—C(═O)—V^(1b)— areindependently selected from:

In one specific embodiment the invention provides a compound wherein oneof —V^(1a)—C(═O)—P^(1a)- and —P^(1b)—C(═O)—V^(1b)— is:

and the other of —V^(1a)—C(═O)—P^(1a)- and —P^(1b)—C(═O)—V^(1b)— is:

In one specific embodiment the invention provides a compound of formula:

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound of formula:

or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides a compound prepared inthe Examples herein that is a compound of specific Embodiment E, or asalt or a prodrug thereof.

In one specific embodiment the invention provides the compound ofExample 538, 544, 555, 561, 562, 572, 587, 589, 590, 592, 594, 599, 606,608, 610, 614, 615, 617, 622, 625, 627, 637, or 639, or apharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides the compound ofExample 506, 519, 527, or 591 or a pharmaceutically acceptable salt orprodrug thereof.

In one specific embodiment the invention provides the compound ofExample 451, 453, 472, 509, 528, 529, 554, 559, 560, or 568, or apharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment the invention provides the compound ofExample 460, 520, 564, 586, 596, 611, or 616 or a pharmaceuticallyacceptable salt or prodrug thereof.

In one specific embodiment the invention provides the compound ofExample 433, 442, or 446, or a pharmaceutically acceptable salt orprodrug thereof.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES Example A

(S)-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

1,4-Dioxane (300 mL) was added to a mixture of(S)-2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (21.1 g, 53.7 mmol), bis(pinacolato)diboron(27.3g, 107.5 mmol), tetrakis(triphenylphosphine)palladium (0) (3.10 g,2.68 mmol), and potassium acetate (15.02 g, 153.0 mmol), and heated at80° C. for 16 hours. The mixture was cooled and the resulting solid wasfiltered. The majority of the 1,4-dioxane was removed from the filtrateunder reduced pressure and resulting residue was taken up in ethylacetate (300 mL). The organic phase was washed with saturated sodiumbicarbonate (2×150 mL), brine (100 mL) and dried over sodium sulfate.After filtration the solvent was removed from the filtrate under reducedpressure. The resulting oil was subjected to silica gel chromatographyusing a 330 g Isco column and effluent of 20-100% ethyl acetate andhexanes. The fractions containing product were combined and the solventwas removed under reduced pressure to provide(S)-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (18 g, 76%) and light yellow solid.

Example AA

(S)-tert-butyl2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of methyl(S)-1-((2S,4S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-4-hydroxypyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(100 mg, 0.19 mmol) in DME (2 mL) was added (S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(83 mg, 0.19 mmol), Pd(PPh₃)₄ (22 mg, 0.019 mmol), and K₂CO₃ (2M in H₂O,0.32 mL, 0.63 mmol). The solution was degassed with N₂ for 10 min, thenheated to 85° C. for 18 h. The mixture was cooled to rt, diluted withEtOAc, and washed with sat. NaHCO₃, brine, dried over MgSO₄, andconcentrated. The residue was purified by silica gel chromatography toyield product (61 mg).

Methyl(R)-2-((S)-2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

To (S)-tert-butyl2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(61 mg, 0.082 mmol) in MeOH (2.5 mL) was added HCl (4M in dioxane, 0.5mL). The solution stirred o/n, and the solvent was removed. Theintermediate was dissolved in DMF (2 mL).(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (19 mg, 0.09 mmol),COMU (39 mg, 0.082 mmol), and DIPEA (0.07 mL, 0.41 mmol) were addedsequentially. The solution was stirred o/n and the mixture was purifiedby HPLC to yield product (15.5 mg). LCMS-ESI⁺: calc'd for C₄₇H₅₀N₈O₇:838.95 (M⁺). Found: 839.29 (M+H⁺).

Example AB

(2S,4S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl4-hydroxypyrrolidine-1,2-dicarboxylate

To a solution of 2-bromo-1-(4-bromophenyl)ethanone (3.6 g, 12.98 mmol)and (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylicacid (2.0 g, 8.65 mmol) in MeCN (50 mL) was added Et₃N (1.8 mL, 12.98mmol). After 3 h, the solution was diluted with EtOAc, sat. NaHCO₃,brine, dried over MgSO₄, and concentrated. The residue was taken oncrude to yield product (3.1 g).

(2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate

To a solution of (2S,4S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl4-hydroxypyrrolidine-1,2-dicarboxylate (3.1 g, 7.24 mmol) in PhMe (75mL) was added NH₄OAc (5.58 g, 72.38 mmol). The solution was heated toreflux for 4 h. The solution was cooled, and diluted with EtOAc, washedwith H₂O, sat. NaHCO₃, brine, dried over MgSO₄, and concentrated. Theresidue was purified by silica gel chromatography to yield product (250mg).

(2S,4S)-tert-butyl4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-hydroxypyrrolidine-1-carboxylate(250 mg, 0.61 mmol) in DMSO (8 mL) was added bis(pinacolato)diboron (187mg, 0.74 mmol), KOAc (180 mg, 1.84 mmol), and Pd(dppf)₂Cl₂ (45 mg, 0.06mmol). The solution was degassed with N₂ for 10 min, then heated to 80°C. for 18 h. The solution was cooled to rt, diluted with EtOAc, washedwith sat. NaHCO₃, brine, dried over MgSO₄, and concentrated. Purified bysilica gel chromatography to yield the product (112 mg).

(2S,4S)-tert-butyl4-hydroxy-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(2S,4S)-tert-butyl4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(200 mg, 0.44 mmol) and methyl(S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(219 mg, 0.44 mmol) were combined in DME (5 mL). Pd(PPh₃)₄ (51 mg,0.0446 mmol) and K₂CO₃ (2M H₂O, 0.73 mL, 1.45 mmol) were added, and thesolution was degassed with N₂ for 10 min. The solution was heated to 85°C. and stirred o/n. The following morning, the solution was cooled tort. The solution was diluted with EtOAc, washed with sat. NaHCO₃, brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel chromatography to yield product (36 mg).

Methyl(R)-2-((S)-2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

To (2S,4S)-tert-butyl4-hydroxy-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(36 mg, 0.048 mmol) in DCM (2.5 mL) and MeOH (1 mL) was added HCl (4M indioxane, 0.25 mL). The solution stirred for 3 h, and the solvent wasremoved. The residue was dissolved in DMF (1 mL).(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (11 mg, 0.05 mmol),COMU (23 mg, 0.048 mmol), and DIPEA (0.04 mL, 0.24 mmol) were addedsequentially. The solution stirred o/n and the mixture was purified byHPLC to yield product (6.9 mg). LCMS-ESI⁺: calc'd for C₄₇H₅₀N₈O₇: 838.95(M⁺). Found: 840.38 (M+H⁺).

Example AC

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-phenyl-2-((R)-tetrahydrofuran-2-carboxamido)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

To a 0° C. solution of methyl(S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-amino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(70 mg, 0.08 mmol) in DMF (1 mL) was added(S)-tetrahydrofuran-2-carboxylic acid (10 mg, 0.09 mmol), PyBOP (52 mg,0.10 mmol), HOBT (14 mg, 0.10 mmol), and N-methylmorpholine (40 mg, 0.4mmol) successively. The solution was warmed to rt and allowed to stirfor 2 h. The mixture was diluted with EtOAc, washed with 1N HCl, sat.NaHCO₃, and brine, dried over MgSO₄, and concentrated. The residue waspurified by silica gel chromatography to yield product (9.5 mg).LCMS-ESI⁺: calc'd for C₅₀H₅₄N₈O₆: 863.01 (M⁺). Found: 863.31 (M+H⁺).

Example AD

(S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butylindoline-1,2-dicarboxylate

To a solution of (S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid(1.61 g, 6.11 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (2.55 g, 9.17mmol) in MeCN (25 mL) was added Et₃N (1.27 mL, 9.17 mmol). The solutionwas heated to 55° C. and stirred o/n. The solution was cooled to rt,diluted with EtOAc, sat. NaHCO₃, brine, dried with MgSO₄, andconcentrated. The residue was taken onto the next step crude.

(S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)indoline-1-carboxylate

To a solution of (S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butylindoline-1,2-dicarboxylate (2.81 g, 6.1 mmol) in PhMe (7 mL) was addedNH₄OAc (4.7 g, 61.0 mmol). The solution was heated to reflux for 3 h.The solution was cooled, and diluted with EtOAc, washed with H₂O, sat.NaHCO₃, brine, dried over MgSO₄, and concentrated. The residue waspurified by silica gel chromatography to yield product (1.41 g).

Methyl(S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

To (S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)indoline-1-carboxylate (1.41 g,3.2 mmol) in DCM (20 mL) was added HCl (4M in dioxane, 4 mL). Thesolution stirred for 2 h, and the solvent was removed. The intermediatewas dissolved in DMF (30 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (560 mg, 3.2 mmol),HATU (1.22 g, 3.2 mmol), and DIPEA (2.79 mL, 16 mmol) were addedsequentially. The solution stirred for 3 h, diluted with EtOAc, washedwith sat. NaHCO₃, brine, dried over MgSO₄, and concentrated. The mixturewas purified by silica gel chromatography to yield product (600 mg).

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)indolin-1-yl)butan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(150 mg, 0.3 mmol) in dioxane (5 mL) was added bis(pinacolato)diboron(92 mg, 0.36 mmol), KOAc (89 mg, 0.09 mmol), and Pd(dppf)₂Cl₂ (23 mg,0.03 mmol). The solution was degassed with N₂ for 10 min, then heated to90° C. for 22 h. The solution was cooled to rt, diluted with EtOAc,washed with sat. NaHCO₃, brine, dried over MgSO₄, and concentrated. Thecrude oil was purified by silica gel chromatography to yield the product(107 mg).

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(biphenyl-4,4′-(2-((S)-indolin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)dicarbamate

To a solution of methyl(S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(99 mg, 0.22 mmol) and methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)indolin-1-yl)butan-2-ylcarbamate(107 mg, 0.20 mmol) was added Pd(dppf)₂Cl₂ (15 mg, 0.02 mmol), Pd(PPh₃)₄(23 mg, 0.02 mmol), and K₂CO₃ (2M H₂O, 0.33 mL, 0.66 mmol). The solutionwas degassed for 10 min, and then heated to 80° C. The solution wasstirred for 18 h, then cooled to rt. The mixture was diluted with MeOH,filtered, and purified by HPLC to yield product (9.0 mg). LCMS-ESI⁺:calc'd for C₄₄H₅₀N₈O₆: 786.92 (M⁺). Found: 787.31 (M+H⁺).

Example AE

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(biphenyl-4,4′-diyl)bis(1H-imidazole-5,2-diyl))bis(indoline-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

To a solution of methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)indolin-1-yl)butan-2-ylcarbamate(130 mg, 0.24 mmol) and methyl(S)-1-((S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(150 mg, 0.30 mmol) was added Pd(PPh₃)₄ (28 mg, 0.024 mmol),Pd(dppf)₂Cl₂ (18 mg, 0.024 mmol) and K₂CO₃ (2M H₂O, 0.4 mL, 0.79 mmol).The solution was degassed for 10 min, and then heated to 85° C. Thesolution was stirred for 18 h, then cooled to rt. The mixture wasdiluted with MeOH, filtered, and purified by HPLC to yield product (114mg). LCMS-ESI⁺: calc'd for C₄₈H₅₀N₈O₆: 834.96 (M⁺). Found: 836.41(M+H⁺).

Example AF

2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,9,10-tetrahydropyrene

To a solution of 2,7-dibromo-4,5,9,10-tetrahydropyrene (400 mg, 1.1mmol) in dioxane (10 mL) was added bis(pinacolato)diboron (614 mg, 2.42mmol), KOAc (648 mg, 6.6 mmol), and Pd(dppf)₂Cl₂ (161 mg, 0.22 mmol).The solution was degassed with N₂ for 10 min, then heated to 90° C. for4 h. The solution was cooled to rt, diluted with EtOAc, washed with sat.NaHCO₃, brine, dried over MgSO₄, and concentrated. Purified by silicagel chromatography (5% EtOAc/hexanes) to yield the product (188 mg).

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(4,5,9,10-tetrahydropyrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

To a solution of2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,9,10-tetrahydropyrene(188 mg, 0.41 mmol) in DME (5 mL) was added methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(306 mg, 0.82 mmol), Pd(PPh₃)₄ (95 mg, 0.08 mmol), and K₂CO₃ (2M H₂O,0.82 mL, 1.64 mmol). The solution was degassed for 10 min, then heatedto 85° C. The solution was stirred for 24 h, then cooled to rt. Themixture was diluted with MeOH, filtered, and purified by HPLC to yieldproduct (8.9 mg). LCMS-ESI⁺: calc'd for C₄₄H₅₄N₈O₆: 790.95 (M⁺). Found:791.40 (M+H⁺).

Example AG

(2S,2′S)-tert-butyl2,2′-(5,5′-(4,5,9,10-tetrahydropyrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

To a solution of 2,7-dibromo-4,5,9,10-tetrahydropyrene (873 mg, 2.4mmol) in dioxane (30 mL) was added bis(pinacolato)diboron (1.46 mg, 5.75mmol), Pd(dppf)₂Cl₂ 351 mg, 0.48 mmol), and KOAc (1.41 mg, 14.4 mmol).The solution was degassed with N₂ for 10 min, and then the sealed tubewas heated to 90° C. for 8 h. The reaction mixture was cooled to rt,then (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.67 g, 5.28mmol), Pd(PPh₃)₄ (555 mg, 0.48 mmol), and K₂CO₃ (2M in H₂O, 7.2 mL, 14.4mmol) was added with DMSO (30 mL). The solution was degassed with N₂ for10 min, then the tube was sealed and heated to 100° C. for 14 h. Themixture was cooled to rt, diluted with EtOAc, and washed with sat.NaHCO₃, brine, dried over MgSO₄, and concentrated. The residue waspurified by silica gel chromatography to yield product (115 mg).

Dimethyl(2S,2′S,3R,3′R)-1,1′-((2S,2′S)-2,2′-(5,5′-(4,5,9,10-tetrahydropyrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate

To (2S,2′S)-tert-butyl2,2′-(5,5′-(4,5,9,10-tetrahydropyrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(115 mg, 0.17 mmol) in DCM (2.5 mL) and MeOH (2.5 mL) was added HCl (4Min dioxane, 1 mL). The solution stirred for 1 h, and the solvent wasremoved. The residue (81 mg, 0.17 mmol) was dissolved in DMF (4 mL).(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (71 mg, 0.37mmol), HATU (139 mg, 0.36 mmol), and DIPEA (0.3 mL, 1.7 mmol) were addedsequentially. The solution was stirred for 3 h and the mixture waspurified by HPLC to yield product (15.6 mg). LCMS-ESI⁺: calc'd forC₄₄H₅₄N₈O₈: 822.95 (M⁺). Found: 824.27 (M+H⁺).

Example AH

Triphenylene-2,7-diol

2,7-dimethoxytriphenylene (358 mg, 1.24 mmol) and pyridine hydrochloride(1.72 g, 14.9 mmol) were heated in a flask to 185° C. for 5 h. Aftercooling to rt, the remaining solid was diluted with H₂O and EtOAc,separated, dried, and concentrated. Taken on crude.

Triphenylene-2,7-diyl bis(trifluoromethanesulfonate)

Triphenylene-2,7-diol (314 mg, 1.2 mmol) was dissolved in DCM (13 mL)and pyridine (1 mL). The solution was cooled to 0° C. and Tf₂O (0.48 mL,2.65 mmol) was added dropwise. After stirring for 2 h, the reactionmixture was poured into HCl (1N) and extracted with DCM. The organiclayer was washed with brine, dried over MgSO₄, and concentrated. Takenon crude.

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(triphenylene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

To a solution of triphenylene-2,7-diyl bis(trifluoromethanesulfonate)(200 mg, 0.38 mmol) in dioxane (5 mL) was added bis(pinacolato)diboron(231 mg, 0.91 mmol), Pd(dppf)₂Cl₂ (56 mg, 0.076 mmol), and KOAc (223 mg,2.28 mmol). The solution was degassed with N₂ for 10 min, and then thesealed tube was heated to 90° C. for 18 h. The reaction mixture wascooled to rt, then methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(313 mg, 0.84 mmol), Pd(PPh₃)₄ (88 mg, 0.076 mmol), and K₂CO₃ (2M inH₂O, 1.14 mL, 2.28 mmol) was added with DMSO (5 mL). The solution wasdegassed with N₂ for 10 min, then the tube was sealed and heated to 100°C. for 23 h. The mixture was cooled to rt, diluted with EtOAc, andwashed with sat. NaHCO₃, brine, dried over MgSO₄, and concentrated. Theresidue was purified by silica gel chromatography (0-30% MeOH/EtOAc) andthen purified by HPLC to yield product (32.1 mg). LCMS-ESI⁺: calc'd forC₄₆H₅₂N₈O₆: 812.96 (M⁺). Found: 814.74 (M+H⁺).

Example AI

(1R,4S)-3-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-tert-butyl-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

To a solution of 2,6-dibromo-3,4-dihydronaphthalen-1(2H)-one (6.75 g,22.21 mmol) and(1R,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (8.04 g, 33.32 mmol) in MeCN (100 mL) was added Et₃N (4.64 mL,33.32 mmol). The solution was heated to 55° C. and stirred o/n. Thesolution was cooled to rt, diluted with EtOAc, sat. NaHCO₃, brine, driedover MgSO₄, and concentrated. The residue was purified by silica gelchromatography to yield product (6.6 g).

(1R,3S,4S)-tert-butyl-3-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a solution of(1R,4S)-3-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-tert-butyl-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate(6.6 g, 14.21 mmol) in PhMe (200 mL) was added NH₄OAc (21.9 g, 284.2mmol). The solution was heated to reflux for 4 h. The solution wascooled, and diluted with EtOAc, washed with H₂O, sat. NaHCO₃, brine,dried over MgSO₄, and concentrated. The residue was purified by silicagel chromatography to yield product (2.4 g).

(1R,3S,4S)-tert-butyl-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

(1R,3S,4S)-tert-butyl-3-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(1.25 g, 2.81 mmol) was diluted in benzene (50 mL). DDQ (0.7 g, 3.1mmol) was added and the solution was heated to reflux for 1.5 h. Aftercooling, the reaction mixture was concentrated and the residue waspurified by silica gel chromatography to yield product (1.1 g).

(1R,3S,4S)-tert-butyl-3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(526 mg, 1.06 mmol) and(1R,3S,4S)-tert-butyl-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(427 mg, 0.96 mmol) were combined in DME (10 mL). Pd(PPh₃)₄ (111 mg,0.096 mmol) and K₂CO₃ (2M H₂O, 1.6 mL, 3.17 mmol) were added, and thesolution was degassed with N₂ for 10 min. The solution was heated to 85°C. and stirred o/n. The following morning, the solution was cooled tort. The solution was diluted with EtOAc, washed with sat. NaHCO₃, brine,dried with MgSO₄, and concentrated. The residue was purified by silicagel chromatography to yield product (280 mg).

Methyl(S)-3-methyl-1-((1R,3S,4S)-3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-met-hylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamate

To (1R,3S,4S)-tert-butyl3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL).The solution stirred for 2 h, and the solvent was removed. Theintermediate (80 mg, 0.13 mmol) was dissolved in DMF(2 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (22 mg, 0.13 mmol),HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol) were addedsequentially. The solution stirred o/n and the mixture was purified byHPLC to yield product (51.8 mg). LCMS-ESI⁺: calc'd for C₄₄H₅₄N₈O₅:786.96 (M⁺). Found: 789.23 (M+H⁺).

Example AJ

Methyl(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamate

To (1R,3 S,4S)-tert-butyl3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL).The solution stirred for 2 h, and the solvent was removed. Theintermediate (80 mg, 0.13 mmol) was dissolved in DMF(2 mL).(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (24 mg, 0.13mmol), HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol) wereadded sequentially. The solution stirred o/n and the mixture waspurified by HPLC to yield product (54.6 mg). LCMS-ESI⁺: calc'd forC₄₄H₅₂N₈O₇: 804.93 (M⁺). Found: 806.23 (M+H⁺).

Example AK

Methyl(S)-2-((1R,3S,4S)-3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

To (1R,3 S,4S)-tert-butyl3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL).The solution stirred for 2 h, and the solvent was removed. Theintermediate (80 mg, 0.13 mmol) was dissolved in DMF (2 mL).(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (28mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol)were added sequentially. The solution stirred o/n and the mixture waspurified by HPLC to yield product (24.6 mg). LCMS-ESI⁺: calc'd forC₄₆H₅₄N₈O₇: 830.97 (M⁺). Found: 831.33 (M+H⁺).

Example AL

Methyl(S)-1-((1R,3S,4S)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(1R,3 S,4S)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(200 mg, 0.45 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL).The solution stirred for 1 h, after which the solvent was removed. Theintermediate (154 mg, 0.45 mmol) was dissolved in DMF (5 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (79 mg, 0.45 mmol),HATU (171 mg, 0.45 mmol), and DIPEA (0.39 mL, 2.25 mmol) were addedsequentially. After stirring o/n, the solution was diluted with EtOAc,washed with sat. NaHCO₃, brine, dried with MgSO₄, and concentrated. Themixture was purified by silica gel chromatography to yield product (122mg).

(S)-tert-butyl2-(5-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Methyl (S)-1-((1R,3S,4S)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(122 mg, 0.24 mmol) and (S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(114 mg, 0.26 mmol) were combined in DME (3 mL). Pd(PPh₃)₄ (28 mg, 0.024mmol) and K₂CO₃ (2M H₂O, 0.4 mL, 0.79 mmol) were added, and the solutionwas degassed with N₂ for 10 min. The solution was heated to 85° C. andstirred o/n. The following morning, the solution was cooled to rt. Thesolution was diluted with EtOAc, washed with sat. NaHCO₃, brine, driedwith MgSO₄, and concentrated. The residue was purified by silica gelchromatography to yield product (73 mg).

Methyl(2S,3R)-3-methoxy-1-((S)-2-(5-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate

(S)-tert-butyl 2-(5-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(73 mg, 0.10 mmol) in DCM (3 mL) and MeOH (3 mL) was added HCl (4M indioxane, 0.5 mL). The solution stirred for 3 h at 35° C., after whichthe solvent was removed. The intermediate (31 mg, 0.13 mmol) wasdissolved in DMF (1 mL).(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (9 mg, 0.05mmol), HATU (19 mg, 0.05 mmol), and DIPEA (0.04 mL, 0.25 mmol) wereadded sequentially. The solution stirred o/n and the mixture waspurified by HPLC to yield product (23.1 mg). LCMS-ESI⁺: calc'd forC₄₄H₅₂N₈O₇: 804.93 (M⁺). Found: 806.34 (M+H⁺).

Example AM

Methyl(S)-2-((S)-2-(5-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-y)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

(S)-tert-butyl 2-(5-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(73 mg, 0.10 mmol) in DCM (3 mL) and MeOH (3 mL) was added HCl (4M indioxane, 0.5 mL). The solution stirred for 3 h at 35° C., after whichthe solvent was removed. The intermediate (31 mg, 0.13 mmol) wasdissolved in DMF (1 mL).(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (16mg, 0.05 mmol), HATU (19 mg, 0.05 mmol), and DIPEA (0.04 mL, 0.25 mmol)were added sequentially. The solution stirred o/n and the mixture waspurified by HPLC to yield product (27.6 mg). LCMS-ESI⁺: calc'd forC₄₆H₅₄N₈O₇: 830.97 (M⁺). Found: 832.56 (M+H⁺).

Example AN

(S)-tert-butyl2-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of 2,7-dibromo-4,5,9,10-tetrahydropyrene (873 mg, 2.4mmol) in dioxane (30 mL) was added bis(pinacolato)diboron (1.46 mg, 5.75mmol), Pd(dppf)₂Cl₂ (351 mg, 0.48 mmol), and KOAc (1.41 mg, 14.4 mmol).The solution was degassed with N₂ for 10 min, and then the sealed tubewas heated to 90° C. for 8 h. The reaction mixture was cooled to rt,then (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.67 g, 5.28mmol), Pd(PPh₃)₄ (555 mg, 0.48 mmol), and K₂CO₃ (2M in H₂O, 7.2 mL, 14.4mmol) was added with DMSO (30 mL). The solution was degassed with N₂ for10 min, then the tube was sealed and heated to 100° C. for 14 h. Themixture was cooled to rt, diluted with EtOAc, and washed with sat.NaHCO₃, brine, dried with MgSO₄, and concentrated. The residue waspurified by silica gel chromatography to yield product (699 mg).

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

To (S)-tert-butyl2-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(300 mg, 0.53 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL).The solution stirred for 1 h, and the solvent was removed. Theintermediate (247 mg, 0.53 mmol) was dissolved in DMF (5 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (93 mg, 0.53 mmol),HATU (200 mg, 0.53 mmol), and DIPEA (0.46 mL, 2.65 mmol) were addedsequentially. The solution was stirred o/n. The mixture was diluted withEtOAc, and washed with sat. NaHCO₃, brine, dried with MgSO₄, andconcentrated. and the mixture was purified by silica gel chromatographyto yield product (139 mg).

(S)-tert-butyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(139 mg, 0.22 mmol) and (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (77 mg, 0.24 mmol)were dissolved in dioxane (2 mL) and DMSO (2 mL). Pd(dppf)₂Cl₂ (16 mg,0.022 mmol), Pd(PPh₃)₄ (25 mg, 0.022 mmol), and K₂CO₃ (2M in H₂O, 0.33mL, 0.66 mmol). The tube was sealed and heated to 100° C. for 20 h. Themixture was cooled to rt, diluted with EtOAc, and washed with sat.NaHCO₃, brine, dried with MgSO₄, and concentrated. The residue waspurified by silica gel chromatography to yield product (54.5 mg).

Methyl(S)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

To (S)-tert-butyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(55 mg, 0.08 mmol) in DCM (3 mL) was added HCl (4M in dioxane, 0.25 mL).The solution stirred for 1 h, and the solvent was removed. Theintermediate was dissolved in DMF (2 mL).(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (16mg, 0.08 mmol), HATU (29 mg, 0.08 mmol), and DIPEA (0.06 mL, 0.37 mmol)were added sequentially. The solution was stirred o/n and the mixturewas purified by HPLC to yield product (17.9 mg). LCMS-ESI⁺: calc'd forC₄₆H₅₆N₈O₇: 832.99 (M⁺). Found: 833.25 (M+H⁺).

Example AO

Methyl(S)-1-((S)-2-(7-(6-bromobenzo[b]thiophen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

To a solution of methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(251 mg, 0.48 mmol) in DME (5 mL) was added6-bromo-2-iodobenzo[b]thiophene (82 mg, 0.24 mmol), Pd(PPh₃)₄ (28 mg,0.024 mmol), and K₂CO₃ (2M in H₂O, 0.8 mL, 1.58 mmol). The solution wasdegassed with N₂ for 10 min, then heated to 85° C. for 24 h. The mixturewas cooled to rt, diluted with EtOAc, and washed with sat. NaHCO₃,brine, dried with MgSO₄, and concentrated. The residue was purified bysilica gel chromatography to yield product (221 mg).

(S)-tert-butyl2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of methyl(S)-1-((S)-2-(7-(6-bromobenzo[b]thiophen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(221 mg, 0.37 mmol) in dioxane (5 mL) was added bis(pinacolato)diboron(111 mg, 0.44 mmol), Pd(dppf)₂Cl₂ (27 mg, 0.037 mmol), and KOAc (107 mg,1.1 mmol). The solution was degassed with N₂ for 10 min, and then thesealed tube was heated to 90° C. for 18 h. The reaction mixture wascooled to rt, then methyl (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (127 mg, 0.4mmol), Pd(PPh₃)₄ (43 mg, 0.037 mmol), and K₂CO₃ (2M in H₂O, 0.54 mL, 1.1mmol) was added with DMSO (5 mL). The solution was degassed with N₂ for10 min, then the tube was sealed and heated to 100° C. for 23 h. Themixture was cooled to rt, diluted with EtOAc, and washed with sat.NaHCO₃, brine, dried with MgSO₄, and concentrated. The residue waspurified by silica gel chromatography to yield product (52.8 mg).

Methyl(R)-2-((S)-2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

To (S)-tert-butyl2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(53 mg, 0.07 mmol) in DCM (3 mL) was added HCl (4M in dioxane, 0.25 mL).The solution stirred for 1 h, and the solvent was removed. Theintermediate was dissolved in DMF (2 mL).(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (15 mg, 0.07 mmol),COMU (36 mg, 0.08 mmol), and DIPEA (0.06 mL, 0.35 mmol) were addedsequentially. The solution was stirred o/n and the mixture was purifiedby HPLC to yield product (14.8 mg). LCMS-ESI⁺: calc'd for C₄₇H₄₈N₈O₆S:853.00 (Me). Found: 853.22 (M+H⁺).

Example AP

(1R,3S,4S)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

(1R,3S,4S)-tert-butyl-3-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(660 mg, 1.35 mmol) in dioxane (13 mL) was added bis(pinacolato)diboron(411 mg, 1.2 mmol), KOAc (398 mg, 4.08 mmol), and Pd(dppf)₂Cl₂ (99 mg,0.135 mmol). The solution was degassed with N₂ for 10 min, then heatedto 90° C. for 2 h. The solution was cooled to rt, diluted with EtOAc,washed with sat. NaHCO₃, brine, dried with MgSO₄, and concentrated.Purified by silica gel chromatography to yield the product (552 mg).

(1R,3S,4S)-tert-butyl-3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Methyl(S)-1-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(482 mg, 1.02 mmol) and (1R,3S,4S)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(552 mg, 1.12 mmol) were combined in DME (12 mL). Pd(PPh₃)₄ (118 mg,0.102 mmol) and K₂CO₃ (2M H₂O, 1.68 mL, 3.36 mmol) were added, and thesolution was degassed with N₂ for 10 min. The solution was heated to 85°C. and stirred o/n. The following morning, the solution was cooled toit. The solution was diluted with EtOAc, washed with sat. NaHCO₃, brine,dried with MgSO₄, and concentrated. The residue was purified by silicagel chromatography to yield product (307 mg).

Methyl(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl))-4,5-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamate

To(1R,3S,4S)-tert-butyl-3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(307 mg, 0.41 mmol) in DCM (5 mL) and MeOH (1 mL) was added HCl (4M indioxane, 1 mL). The solution stirred for 2 h, and the solvent wasremoved. The intermediate (133 mg, 0.2 mmol) was dissolved in DMF (2.5mL). (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (38 mg, 0.2mmol), HATU (76 mg, 0.2 mmol), and DIPEA (0.18 mL, 1.0 mmol) were addedsequentially. The solution stirred o/n and the mixture was purified byHPLC to yield product (104.1 mg). LCMS-ESI⁺: calc'd for C₄₆H₅₄N₈O₇:830.97 (M⁺). Found: 832.39 (M+H⁺).

Example AQ

Methyl(S)-2-((1R,3S,4S)-3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

To(1R,3S,4S)-tert-butyl-3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(307 mg, 0.41 mmol) in DCM (5 mL) and MeOH (1 mL) was added HCl (4M indioxane, 1 mL). The solution stirred for 2 h, and the solvent wasremoved. The intermediate (133 mg, 0.2 mmol) was dissolved in DMF (2.5mL). ((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)aceticacid (43 mg, 0.2 mmol), HATU (76 mg, 0.2 mmol), and DIPEA (0.18 mL, 1.0mmol) were added sequentially. The solution stirred o/n and the mixturewas purified by HPLC to yield product (100.8 mg). LCMS-ESI⁺: calc'd forC₄₈H₅₆N₈O₇: 857.01 (M⁺). Found: 857.42 (M+H⁺).

Example AR

2-tert-Butoxycarbonylamino-3-difluoromethoxy-butyric acid methyl ester

To a mixture of 2-tert-butoxycarbonylamino-3-hydroxy-butyric acid methylester (630 mg, 2.70 mmol) and copper(I) iodide (105 mg, 0.55 mmol) inacetonitrile at 45° C. was added a solution of2-(fluorosulfonyl)difluoroacetic acid (0.560 mL, 5.42 mmol) inacetonitrile (2 mL) by syringe pump over 45 minutes. The reaction wasthen stirred at 45° C. for 30 minutes. Another solution of2-(fluorosulfonyl)difluoroacetic acid (0.560 mL, 5.42 mmol) inacetonitrile (2 mL) was added by syringe pump over 45 minutes at 45° C.The reaction was stirred for 30 minutes at 45° C. after the secondsyringe pump addition was complete. Water was carefully added to quenchthe reaction, and the mixture was diluted with ethyl acetate. Theorganic layer was separated, washed with water and brine, dried (MgSO₄)and concentrated. The crude material was purified by flashchromatography (10% ethyl acetate/hexanes) to yield2-tert-butoxycarbonylamino-3-difluoromethoxy-butyric acid methyl ester(276 mg, 36%). ¹H-NMR: 400 MHz, (CDCl₃: 6.16 (t, J_(HF)=74.0 Hz, 1H),5.23-5.16 (br, 1H), 4.86-4.80 (m, 1H), 4.40 (br d, J=9.8 Hz, 1H), 3.76(s, 3H), 1.46 (br s, 9H), 1.36 (d, J=6.4 Hz, 3H) ppm.

(2S,3R)-methyl-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoate

To a solution of 2-tert-Butoxycarbonylamino-3-difluoromethoxy-butyricacid methyl ester (3 g, 10.6 mmol) in methanol (40 mL) was addedconcentrated HCl solution (10 mL) and the reaction was stirred at 50° C.for 1 hour. The reaction was concentrated on a rotary evaporator and theresulting residue was basified with saturated NaHCO₃ solution. Theaqueous layer was extracted twice with ethyl acetate. The organic layerwas separated, washed with brine, dried (MgSO4) and concentrated. To asolution of the crude material in dichloromethane (50 mL) was addeddiisopropylethylamine (4.2 mL, 24.2 mmol), followed by methylchloroformate (0.95 mL, 12.3 mmol). The reaction was stirred at roomtemperature for 2 hours, quenched by the careful addition of saturatedNH₄Cl solution and diluted with ethyl acetate. The organic layer wasseparated, washed with water and brine, dried (MgSO₄) and concentrated.The crude material was purified by flash chromatography to yield(2S,3R)-methyl-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoate(1.2 g, 47%).

(2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoic acid

To a solution of(2S,3R)-methyl-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoate(265 mg, 1.1 mmol) in dichloroethane (10 mL) was added trimethyltinhydroxide (1 g, 5.5 mmol) and the resulting mixture was heated to 80° C.for 1 hour. The reaction was cooled to room temperature, diluted withethyl acetate, washed twice with 5% aqueous HCl solution and brine,dried (MgSO₄) and concentrated. The resulting crude material (209 mg,84%) was used without further purification.

Methyl(2S,3R)-3-(difluoromethoxy)-1-oxo-1-((S)-2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

To a solution of(2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoic acid (205mg, 0.9 mmol) and(S)-2-(pyrrolidin-2-yl)-5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazole(315 mg, 0.8 mmol) in dimethylformamide (8 mL) was added HATU (325 mg,0.85 mmol) and diisopropylethylamine (0.565 mL, 3.2 mmol). The reactionwas stirred for 1 hour and then diluted with ethyl acetate. The organiclayer was washed twice with saturated NaHCO₃ solution and brine, dried(MgSO₄) and concentrated. The resulting residue was purified by falshchromatography to yield methyl(2S,3R)-3-(difluoromethoxy)-1-oxo-1-((S)-2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(230 mg, 47%). LCMS-ESI⁺: calculated for C₃₀H₃₇BF₂N₄O₆: 598.45. observed[M+1]⁺: 599.31.

(S)-tert-butyl2-(5-(4-(6-(2-((S)-1-((2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of methyl(2S,3R)-3-(difluoromethoxy)-1-oxo-1-((S)-2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(120 mg, 0.20 mmol), (S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (87 mg,0.22 mmol), and tetrakistriphenylphosphine palladium(0) (23 mg, 0.020mmol) in dimethoxyethane (2 mL) was added a 2M aqueous potassiumcarbonate solution (0.40 mL, 0.80 mmol). The mixture was degassed with astream of argon for 15 minutes, and then heated to 85° C. for threehours. The reaction was diluted with ethyl acetate, cooled to roomtemperature and filtered through Celite. The filtrate was washed withwater and brine, dried (MgSO₄) and concentrated. The resulting residuewas purified by flash chromatography to yield (S)-tert-butyl2-(5-(4-(6-(2-((S)-1-((2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(70 mg, 45%). LCMS-ESI⁺: calculated for C₄₂H₄₇F₂N₇O₆: 783.86. observed[M+1]⁺: 784.72.

Methyl(2S,3R)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-(difluoromethoxy)-1-oxobutan-2-ylcarbamate

A solution of (S)-tert-butyl2-(5-(4-(6-(2-((S)-1-((2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(68 mg, 0.09 mmol), dichloromethane (1 mL), 4M HCl in dioxane (0.07 mL,0.28 mmol) and dimethylformamide (0.1 mL) was stirred at roomtemperature for one hour. Dichloromethane (5 mL) was added to thereaction and then concentrated to a solid. Dilution with dichloromethaneand concentration was repeated a total of three times. The resultingsolid was dissolved in methanol and filtered through a freebasing column(Stratospheres™ PL-HCO₃MP SPE, Part #: PL3540-C603). The filtrate wasconcentrated and used without further purification. The crude materialwas dissolved in a 4:1 dichloromethane:dimethylformamide solution (0.8mL). To this solution was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (25 mg, 0.12 mmol) andCOMU (41 mg, 0.1 mmol) and the reaction was cooled to 0° C.Diisopropylethylamine (0.045 mL, 0.24 mmol) was added and the reactionwas stirred at 0° C. for one hour. The reaction was diluted with ethylacetate and the organic layer was washed with water and brine, dried(MgSO₄) and concentrated. The resulting residue was purified bypreparative reverse phase HPLC (Gemini, 15 to 50% ACN/H₂O+0.1% HCO₂H) toyield methyl(2S,3R)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-(difluoromethoxy)-1-oxobutan-2-ylcarbamate(34 mg, 45% over 2 steps). LCMS-ESI⁺: calculated for C₄₇H₄₈F₂N₈O₇:874.93. observed [M+1]⁺: 875.78.

Example AS

(6-bromonaphthalen-1-yloxy)triisopropylsilane

To a solution of 6-bromo-1-tetralone (10.6 g, 47.1 mmol) indichloromethane (145 mL) cooled to 0° C. were sequentially addedtriethylamine (12 mL, 86.1 mmol) and triisopropylsilyltrifluoromethanesulfonate (15.3 mL, 56.7 mmol). After stirring for tenminutes, the ice bath was removed and the reaction was allowed to warmto room temperature for 30 minutes. The reaction was diluted with 1:1ethyl acetate:hexanes and the organic layer was washed with water andbrine. The organics were dried (MgSO₄), concentrated, and the resultingmaterial was used without further purification. The crude enolsilane wasdissolved in tetrahydrofuran (470 mL) and cooled to 0° C. To thesolution was added solid 2,3-dichloro-5,6-dicyanobenzoquinone (16 g,70.5 mmol) and the reaction was warmed to room temperature. After 30minutes the reaction was concentrated and the crude material waspurified by flash column chromatography (hexanes) to afford(6-bromonaphthalen-1-yloxy)triisopropylsilane (17.1 g, 96% over 2steps).

2-chloro-1-(5-(triisopropylsilyloxy)-naphthalen-2-yl)ethanone

To a solution of (6-bromonaphthalen-1-yloxy)triisopropylsilane (10.4 g,27.5 mmol) in tetrahydrofuran (180 mL) under argon at −78° C. was addedn-butyllithium (2.5M in hexanes, 11.5 mL, 28.7 mmol). After stirring atthis temperature for one hour, a solution of 2-chloro-N-methoxy-N-methylacetamide (7.6 g, 55.2 mmol) in tetrahydrofuran (10 mL) was added to thereaction via cannula. The dry ice bath was removed and the reaction wasallowed to warm to room temperature. After one hour at room temperaturethe reaction was diluted with ethyl acetate and the organics were washedwith saturated aqueous NH₄Cl solution, water and brine. The organiclayer was dried (MgSO₄) and concentrated, and the resulting residue waspurified by flash chromatography to yield2-chloro-1-(5-(triisopropylsilyloxy)-naphthalen-2-yl)ethanone (7.8 g,75%) as a pale yellow oil.

(S)-1-benzyl 2-(2-(5-hydroxy-naphthalen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate

To a solution of2-chloro-1-(5-(triisopropylsilyloxy)-naphthalen-2-yl)ethanone (7.8 g,20.7 mmol) and N-benzyloxycarbonyl-L-proline (5.4 g, 21.7 mmol) inacetonitrile (105 mL) was added diisopropylethylamine (7.2 mL, 41.4mmol). The reaction was heated to 60° C. for one hour until TLCconfirmed that all of the of2-chloro-1-(5-(triisopropylsilyloxy)-naphthalen-2-yl)ethanone wasconsumed. Then tetrabutylammonium fluoride solution (1M in THF, 41.4 mL,41.4 mmol) was added and the reaction was allowed to stir at 60° C.After one hour at this temperature, the reaction was cooled to roomtemperature and diluted with ethyl acetate and water. The organic layerwas separated, washed with water and brine, dried (MgSO₄) andconcentrated. The crude material was purified by flash columnchromatography to yield (S)-1-benzyl2-(2-(5-hydroxy-naphthalen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (7.1 g, 79%). LCMS-ESI⁺: calculated forC₂₅H₂₃NO₆: 433.15. observed [M+1]⁺: 433.97.

Example AT

(2-bromo-5-iodobenzyloxy)-(tert-butyl)dimethylsilane

To a solution of 2-bromo-5-iodobenzoic acid (11.4 g, 34.8 mmol) indichloromethane (140 mL) was added methanol (17 mL) followed bytrimethylsilyldiazomethane solution (2M in hexanes, 19.2 mL, 38.4 mmol).The reaction was stirred at room temperature for twelve hours, quenchedby the dropwise addition of acetic acid (5 mL) and thoroughlyconcentrated. The resulting residue was dissolved in tetrahydrofuran. Tothis solution was added diisobutylaluminum hydride solution (1M in DCM,50 mL, 50 mmol) and the reaction was stirred at room temperature. Aftersixteen hours, more diisobutylaluminum hydride solution (1M in DCM, 50mL, 50 mmol) was added. After 96 more hours at room temperature thereaction was diluted with ether (100 mL) and quenched by the sequentialaddition of water (4 mL), 15% aqueous NaOH solution (4 mL) and water (10mL). After thirty minutes the mixture was filtered through Celite andthe filtrate was concentrated. The resulting residue was dissolved indimethylformamide (75 mL). To this solution was added imidazole (6.1 g,89.6 mmol) and t-butyldimethylchlorosilane (6.8 g, 45.1 mmol). Thereaction was stirred at room temperature for two hours and then dilutedwith ethyl acetate. The organics were washed with saturated aqueousNH₄Cl solution, water and brine. The organic layer was dried (MgSO₄) andconcentrated, and the resulting residue was purified by flash columnchromatography to yield(2-bromo-5-iodobenzyloxy)-(tert-butyl)dimethylsilane (9.2 g, 62%).

1-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)-2-chloroethanone

To a solution of (2-bromo-5-iodobenzyloxy)-(tert-butyl)dimethylsilane(8.7 g, 20.3 mmol) in tetrahydrofuran (135 mL) under argon at −20° C.was added i-propylmagnesium chloride-lithium chloride solution (1.3M inTHF, 16.4 mL, 21.3 mmol). After stirring at this temperature for thirtyminutes, a solution of 2-chloro-N-methoxy-N-methyl acetamide (3.4 g,24.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction viacannula. The reaction was stirred at −20° C. for one hour and thenwarmed to room temperature. After one hour at room temperature thereaction was diluted with ethyl acetate and the organics were washedwith saturated aqueous NH₄Cl solution, water and brine. The organiclayer was dried (MgSO₄) and concentrated, and the resulting residue waspurified by flash chromatography to yield1-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)-2-chloroethanone(5.1 g, 67%).

(S)-2-(2-(4-bromo-3-((methylsulfonyloxy)methyl)phenyl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate

To a solution of1-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)-2-chloroethanone(5.1 g, 13.5 mmol) and N-t-butoxycarbonyl-L-proline (3.8 g, 17.6 mmol)in acetonitrile (68 mL) was added diisopropylethylamine (7.0 mL, 40.5mmol). The reaction was heated to 60° C. for one hour until TLCconfirmed that all of the of1-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)-2-chloroethanonewas consumed. Then tetrabutylammonium fluoride solution (1M in THF, 27.0mL, 27.0 mmol) was added and the reaction was allowed to stir at 60° C.After one hour at this temperature, the reaction was cooled to roomtemperature and diluted with ethyl acetate and water. The organic layerwas separated, washed with water and brine, dried (MgSO₄) andconcentrated. The crude material was purified by flash columnchromatography to yield the free benzyl alcohol (4.7 g, 78%). The benzylalcohol and diisopropylethylamine (6 mL, 34.5 mmol) were dissolved indichloromethane (100 mL). To this solution was added methanesulfonicanhydride (2.3 g, 12.1 mmol) and the reaction was stirred for 45minutes. The reaction was diluted with dichloromethane, and the organicswere washed with water. The organic layer was dried (MgSO₄) andconcentrated, and the resulting residue was purified by flash columnchromatography to yield(S)-2-(2-(4-bromo-3-((methylsulfonyloxy)methyl)phenyl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (5.2 g, 94%).

Example AU

(S)-1-benzyl2-(2-(5-(2-bromo-5-(2-((S)-1-(tert-butoxycarbonyl)-pyrrolidine-2-carbonyloxy)acetyl)benzyloxy)naphthalen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate

To a solution of(S)-2-(2-(4-bromo-3-((methylsulfonyloxy)methyl)phenyl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (5.2 g, 10.0 mmol) and(S)-1-benzyl 2-(2-(5-hydroxy-naphthalen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (4.5g, 10.4 mmol) in dimethylformamide(100 mL) was added cesium carbonate (7.2 g, 22.1 mmol). The mixture wasstirred at room temperature for two hours and diluted with ethylacetate. The organics were washed with water and brine, dried (MgSO₄)and concentrated. The resulting residue was purified by flash columnchromatography to yield (S)-1-benzyl2-(2-(5-(2-bromo-5-(2-((S)-1-(tert-butoxycarbonyl)-pyrrolidine-2-carbonyloxy)acetyl)benzyloxy)naphthalen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (6.3 g, 74%). LCMS-ESI⁺: calculated forC₄₄H₄₅BrN₂O₁₁: 856.22; observed [M+Na]⁺: 879.21.

(S)-1-benzyl2-(2-(8-(2-((S)-1-(tert-butoxycarbonyl)-pyrrolidine-2-carbonyloxy)acetyl)-6H-dibenzo-[c,h]chromen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate

A mixture of (S)-1-benzyl2-(2-(5-(2-bromo-5-(2-((S)-1-(tert-butoxycarbonyl)-pyrrolidine-2-carbonyloxy)acetyl)benzyloxy)naphthalen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (3.7 g, 4.3 mmol), PdCl₂(dppf) (0.63 g,0.86 mmol), sodium acetate (1.1 g, 13.3 mmol) and dimethylformamide (43mL) was degassed with a stream of argon for 15 minutes. The mixture wasthen heated to 110° C. for 6 hours. The reaction was cooled to roomtemperature, diluted with ethyl acetate and water, and the biphasicmixture was filtered through Celite. The organic portion of the filtratewas separated, washed with more water and brine, dried (MgSO₄) andconcentrated. The resulting residue was purified by flash columnchromatography to yield (S)-1-benzyl2-(2-(8-(2-((S)-1-(tert-butoxycarbonyl)-pyrrolidine-2-carbonyloxy)acetyl)-6H-dibenzo-[c,h]chromen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (1.5 g, 46%). LCMS-ESI⁺: calculated forC₄₄H₄₄N₂O₁₁: 776.29. observed [M-BOC+1]⁺: 677.53.

(S)-benzyl2-(5-(8-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of (S)-1-benzyl2-(2-(8-(2-((S)-1-(tert-butoxycarbonyl)-pyrrolidine-2-carbonyloxy)acetyl)-6H-dibenzo-[c,h]chromen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (2.0 g, 2.6 mmol) in toluene (30 mL) wasadded ammonium acetate (3.5 g, 41.7 mmol). The resulting mixture wasvigorously refluxed for three hours. The reaction was cooled to roomtemperature and diluted with ethyl acetate. The organic were washed withwater and brine, dried (MgSO₄) and concentrated. The resulting crudematerial was purified by flash column chromatography to yield (S)-benzyl2-(5-(8-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.2 g, 62%). LCMS-ESI⁺: calculated for C₄₄H₄₄N₆O₅: 736.34. observed[M+1]⁺: 737.27.

(S)-benzyl2-(5-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A solution of (S)-benzyl2-(5-(8-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.2 g, 1.6 mmol), concentrated HCl (1.5 mL) and ethanol (10 mL) washeated to 60° C. for one hour. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offthree more times, until the crude material was a yellow powder. Aportion of the crude amine (0.3 g, ˜0.40 mmol) was dissolved indimethylformamide (4.7 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (125 mg, 0.7 mmol),HATU (270 mg, 0.7 mmol) and diisopropylethylamine (0.82 mL, 4.7 mmol).The reaction was stirred at room temperature for one hour, and thendiluted with acetonitrile (2 mL) and methanol (2 mL). To this solutionwas added ten drops of 5M aqueous NaOH solution and stirring wascontinued for 30 minutes. The reaction was diluted with ethyl acetateand the organic layer was washed with water and brine. The combinedaqueous washings were extracted three times with ethyl acetate, and thecombined organic layers were dried (MgSO₄) and concentrated. The crudematerial was purified by flash column chromatography to yield (S)-benzyl2-(5-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(260 mg, ˜80%). LCMS-ESI⁺: calculated for C₄₆H₄₇N₇O₆: 793.91. observed[M+1]⁺: 794.70.

Methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

A mixture of (S)-benzyl2-(5-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(260 mg, 0.33 mmol), 33% HBr in acetic acid (1 mL) and dichloromethane(4 mL) was vigorously stirred at room temperature for 30 minutes andthen thoroughly concentrated. The crude material was diluted withdichloromethane and concentrated, letting the resulting residue situnder vacuum overnight. To this residue were sequentially addeddichloromethane (2.4 mL), dimethylformamide (0.6 mL),(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (88 mg, 0.42 mmol), andCOMU (154 mg, 0.36 mmol) and diisopropylethylamine (0.16 mL, 0.9 mmol).After stirring for 30 minutes at room temperature the reaction wasdiluted with ethyl acetate and washed sequentially with saturatedaqueous NaHCO₃ solution, water and brine. The organic layer was dried(MgSO₄), then filtered through a freebasing column (Stratospheres™PL-HCO₃MP SPE, Part #: PL3540-C603). The filtrate was concentrated andpurified by preparative reverse phase HPLC (Gemini, 15 to 50%ACN/H₂O+0.1% HCO₂H) to yield methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(72 mg, 26%). LCMS-ESI⁺: calculated for C₄₈H₅₀N₈O₇: 850.96. observed[M+1]⁺: 851.93.

Example AV

methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylaminopropanoyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

Methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylaminopropanoyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate:This compound was made in an analogous manner to methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate,substituting (S)-2-(methoxycarbonylamino)propanoic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amidecoupling. LCMS-ESI⁺: calculated for C₄₆H₄₆N₈O₇: 822.91. observed [M+1]⁺:823.58.

Example AW

methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

Methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate:This compound was made in an analogous manner to methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate,substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amidecoupling. LCMS-ESI⁺: calculated for C₄₈H₅₀N₈O₈: 866.96. observed [M+1]⁺:867.58.

Example AX

methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

Methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate:This compound was made in an analogous manner to methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate,substituting(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amidecoupling. LCMS-ESI⁺: calculated for C₅₀H₅₂N₈O₈: 893.00. observed [M+1]⁺:894.00.

Example AY

methyl(2S,3R)-1-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate

Methyl(2S,3R)-1-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate:This compound was made in an analogous manner to methyl(R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate,substituting(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amidecoupling, and substituting(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amidecoupling. LCMS-ESI⁺: calculated for C₄₇H₅₄N₈O₉: 874.98. observed [M+1]⁺:876.01.

Example AZ

(S)-benzyl2-(5-(4′-chlorobiphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S′)-benzyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4.7 g,11.0 mmol), 4-chlorophenylboronic acid (2.0 g, 12.1 mmol),tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol), 2M aqueouspotassium carbonate solution (22 mL, 44 mmol), and dimethylformamide(100 mL) was degassed under a stream of argon for 15 minutes. Thereaction was heated to 75° C. for 3 hours. Upon completion, the reactionwas cooled to room temperature, diluted with ethyl acetate and filteredthrough Celite. The filtrate was washed with water and brine, dried(MgSO₄) and concentrated. The resulting crude material was purified byflash column chromatography to yield (S)-benzyl2-(5-(4′-chlorobiphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(4.3 g, 85%).

(S)-benzyl2-(5-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-benzyl2-(5-(4′-chlorobiphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(4.3 g, 9.4 mmol), bis(pinacolato)diboron (4.8 g, 18.9 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.44 g, 0.48 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 0.92 g,1.9 mmol), potassium acetate (2.8 g, 28.5 mmol), and dioxane (19 mL) wasdegassed under a stream of argon for 15 minutes. The reaction was heatedto 85° C. for 30 minutes. Upon completion, the reaction was cooled toroom temperature, diluted with ethyl acetate and filtered throughCelite. The filtrate was washed with water and brine, dried (MgSO₄) andconcentrated. The resulting crude material was purified by flash columnchromatography to yield (S)-benzyl2-(5-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(4.6 g, 89%).

(S)-benzyl2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-benzyl2-(5-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(2.1 g, 3.8 mmol), (S)-tert-butyl2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.6 g,4.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.44 mg, 0.38mmol), 2M aqueous potassium carbonate solution (7.7 mL, 15.4 mmol) anddimethoxyethane (26 mL) was degassed under a stream of argon for 15minutes. The reaction was heated to 85 OC for 14 hours. Upon completion,the reaction was cooled to room temperature, diluted with ethyl acetateand filtered through Celite. The filtrate was washed with water andbrine, dried (MgSO₄) and concentrated. The resulting crude material waspurified by flash column chromatography to yield (S)-benzyl2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.2 g, 44%). LCMS-ESI⁺: calculated for C₄₃H₄₄N₆O₄: 708.85. observed[M+1]⁺: 709.41.

(S)-benzyl2-(5-(4′-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A solution of (S)-benzyl2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.6 g, 0.85 mmol), concentrated HCl (1.5 mL) and ethanol (10 mL) washeated to 60° C. for one hour. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offthree more times, until the crude material was a yellow powder. Aportion of the crude amine (0.3 g, ˜0.42 mmol) was dissolved indimethylformamide (4.7 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (165 mg, 0.9 mmol),HATU (355 mg, 0.9 mmol) and diisopropylethylamine (0.82 mL, 4.7 mmol).The reaction was stirred at room temperature for one hour, and thendiluted with acetonitrile (2 mL) and methanol (2 mL). To this solutionwas added ten drops of 5M aqueous NaOH solution and stirring wascontinued for 30 minutes. The reaction was diluted with ethyl acetateand the organic layer was washed with water and brine. The combinedaqueous washings were extracted three times with ethyl acetate, and thecombined organic layers were dried (MgSO₄) and concentrated. The crudematerial was purified by flash column chromatography to yield (S)-benzyl2-(5-(4′-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.28 g, ˜74%). LCMS-ESI⁺: calculated for C₄₅H₄₇N₇O₅: 765.90. observed[M+1]⁺: 766.47.

Methyl(R)-2-((S)-2-(5-(4′-(2-((S)-1-((R)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

To a solution of (S)-benzyl2-(5-(4′-(2-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.28 g, 0.37 mmol), potassium carbonate (105 mg, 0.75 mmol) and water(1 drop) in ethanol (5 mL) was added 10% palladium on carbon (200 mg).The reaction flask was flushed with argon for 2 minutes. Hydrogen gaswas bubbled through the reaction mixture for 10 minutes. The reactionwas stirred under hydrogen gas for 18 hours, and then flushed withargon. The mixture was diluted with methanol and filtered throughCelite. The filtrate was concentrated and used without purification inthe next step. This residue was dissolved in a 5:1 mixture ofdichloromethane:dimethylformamide (4.3 mL) and cooled to 0° C. To thesolution were sequentially added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (98 mg, 0.47 mmol) andCOMU (202 mg, 0.47 mmol). After one hour, the reaction was diluted withacetonitrile (2 mL) and methanol (2 mL). To this solution was added tendrops of 5M aqueous NaOH solution and stirring was continued for 30minutes. The reaction was diluted with ethyl acetate and the organiclayer was washed with water and brine. The combined aqueous washingswere extracted three times with ethyl acetate, and the combined organiclayers were dried (MgSO₄) and concentrated. The crude material waspurified by preparative reverse phase HPLC (Gemini, 15 to 50%ACN/H₂O+0.1% HCO₂H), followed by flash column chromatography to yieldmethyl(R)-2-((S)-2-(5-(4′-(2-((S)-1-((R)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(165 mg, 55%). LCMS-ESI⁺: calculated for C₄₇H₅₀N₈O₆: 822.95. observed[M+1]⁺: 823.87.

Example BA

(S)-tert-butyl2-(6-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution—of (S)-benzyl2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.65 g, 0.92 mmol), potassium carbonate (200 mg, 1.4 mmol) and water (2drops) in ethanol (11.6 mL) was added 10% palladium on carbon (260 mg).The reaction flask was flushed with argon for 2 minutes. Hydrogen gaswas bubbled through the reaction mixture for 10 minutes. The reactionwas stirred under hydrogen gas for 18 hours, and then flushed withargon. The mixture was diluted with methanol and filtered throughCelite. The filtrate was concentrated and used without purification inthe next step. The crude material was dissolved in dimethylformamide(7.4 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (156 mg, 0.9 mmol),HATU (340 mg, 0.9 mmol) and diisopropylethylamine (0.39 mL, 2.2 mmol).The reaction was stirred at room temperature for one hour, and thendiluted with acetonitrile (2 mL) and methanol (2 mL). To this solutionwas added ten drops of 5M aqueous NaOH solution and stirring wascontinued for 30 minutes. The reaction was diluted with ethyl acetateand the organic layer was washed with water and brine. The combinedaqueous washings were extracted three times with ethyl acetate, and thecombined organic layers were dried (MgSO₄) and concentrated. The crudematerial was purified by flash column chromatography to yield(S)-tert-butyl2-(6-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(368 mg, 68%). LCMS-ESI⁺: calculated for C₄₂H₄₉N₇O₅: 731.88. observed[M+1]⁺: 732.75.

Methyl(S)-1-((S)-2-(5-(4′-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of (S)-tert-butyl2-(6-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(368 mg, 0.50 mmol), concentrated HCl (1 mL) and ethanol (6 mL) washeated to 60° C. for one hour. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offthree more times, until the crude material was a yellow powder. Thecrude material was dissolved in a 5:1 mixture ofdichloromethane:dimethylformamide (4.9 mL) and cooled to 0° C. To thesolution are sequentially added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (119 mg, 0.57 mmol),COMU (232 mg, 0.54 mmol) and diisopropylethylamine (0.26 mL, 1.5 mmol).After one hour, the reaction is diluted with acetonitrile (2 mL) andmethanol (2 mL). To this solution was added ten drops of 5M aqueous NaOHsolution and stirring was continued for 30 minutes. The reaction wasdiluted with ethyl acetate and the organic layer was washed with waterand brine. The combined aqueous washings were extracted three times withethyl acetate, and the combined organic layers were dried (MgSO₄) andconcentrated. The crude material was purified by preparative reversephase HPLC (Gemini, 15 to 50% ACN/H₂O+0.1% HCO₂H), followed by flashcolumn chromatography to yield methyl(S)-1-((S)-2-(5-(4′-2-((S)-1-((R)-2-methoxycarbonylamiino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(270 mg, 66%). LCMS-ESI⁺: calculated for C₄₇H₅₀N₈O₆: 822.95. observed[M+1]⁺: 823.90.

Example BB

3,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-dibenzo[b,d]thiophene

A solution of 3,7-dibromodibenzo[b,d]thiophene (5.6 g, 16.4 mmol),bis(pinacolato)diboron (12.5 g, 49.2 mmol) and potassium acetate (9.7 g,98.9 mmol) in 2:1 dioxane:dimethylformamide (165 mL) was degassed forfifteen minutes. To this solution was added PdCl₂(dppf) (1.2 g, 1.6mmol) and the reaction was heated to 85° C. for 2 hours. The mixture wascooled to room temperature, diluted with ethyl acetate and filteredthrough Celite. The filtrate was washed with water and brine, dried(MgSO₄) and concentrated. The resulting residue was quickly passedthrough a silica gel plug. The fractions containing product wereconcentrated and recrystallized from a minimal amount of dichloromethaneand a large amount of methanol to yield3,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-dibenzo[b,d]thiophene(5.1 g, 71%).

(S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of3,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-dibenzo[b,d]thiophene(3.6 g, 8.2 mmol), (S)-tert-butyl2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g,2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.31 mg, 0.27mmol), 2M aqueous potassium carbonate solution (5 mL, 10 mmol),dimethoxyethane (25 mL), toluene (5 mL) and dichloroethane (2.5 mL) wasdegassed under a stream of argon for 15 minutes. The reaction was heatedto 85° C. for 2 hours. Upon completion, the reaction was cooled to roomtemperature, diluted with ethyl acetate and filtered through Celite. Thefiltrate was washed with water and brine, dried (MgSO₄) andconcentrated. The resulting crude material was purified by flash columnchromatography to yield (S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.0 g, 62%).

(S)-benzyl2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(870 mg, 1.5 mmol), (S)-benzyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (620 mg, 1.8mmol), tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.15 mmol),PdCl₂(dppf) (110 mg, 0.15 mmol), 2M aqueous potassium carbonate (2.2 mL,4.4 mmol), dimethoxyethane (12.2 mL) and dimethylformamide (2.4 mL) wasdegassed with argon for 15 minutes. The reaction was then heated to 85°C. for 2 hours. Upon completion, the reaction was cooled to roomtemperature, diluted with ethyl acetate and filtered through Celite. Thefiltrate was washed with water and brine, dried (MgSO₄) andconcentrated. The resulting crude material was purified by flash columnchromatography to yield (S)-benzyl2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(750 mg, 70%). LCMS-ESI⁺: calculated for C₄₃H₄₂N₆O₄S: 738.30. observed[M+1]⁺: 739.19.

(S)-benzyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A solution of (S)-benzyl2-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.75 g, 1.0 mmol), concentrated HCl (2.0 mL) and ethanol (12 mL) washeated to 60° C. for one hour. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offthree more times, until the crude material was a powder. A portion ofthe crude amine (0.29 g, ˜0.40 mmol) was dissolved in dimethylformamide(3.9 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (82 mg, 0.47 mmol),HATU (163 mg, 0.43 mmol) and diisopropylethylamine (0.70 mL, 4.0 mmol).The reaction was stirred at room temperature for one hour, and thendiluted with acetonitrile (2 mL) and methanol (2 mL). To this solutionwas added ten drops of 5M aqueous NaOH solution and stirring wascontinued for 30 minutes. The reaction was diluted with ethyl acetateand the organic layer was washed with water and brine. The combinedaqueous washings were extracted three times with ethyl acetate, and thecombined organic layers were dried (MgSO₄) and concentrated. The crudematerial was purified by flash column chromatography to yield (S)-benzyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.19 g, ˜60%). LCMS-ESI⁺: calculated for C₄₅H₄₅N₇O₅S: 795.95. observed[M+1]⁺: 796.73.

Methyl(R)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

To a solution of (S)-benzyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.19 g, 0.24 mmol), potassium carbonate (70 mg, 0.50 mmol) and water (1drop) in ethanol (3.5 mL) was added 10% palladium on carbon (175 mg).The reaction flask was flushed with argon for 2 minutes. Hydrogen gaswas bubbled through the reaction mixture for 10 minutes. The reactionwas stirred under hydrogen gas for 18 hours, and then flushed withargon. The mixture was diluted with methanol and filtered throughCelite. The filtrate was concentrated and used without purification inthe next step. This residue was dissolved in a 5:1 mixture ofdichloromethane:dimethylformamide (3.0 mL) and cooled to 0° C. To thesolution were sequentially added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (76 mg, 0.36 mmol) andCOMU (150 mg, 0.35 mmol). After one hour, the reaction was diluted withethyl acetate and the organic layer was washed with water and brine. Thecombined aqueous washings were extracted three times with ethyl acetate,and the combined organic layers were dried (MgSO₄) and concentrated. Thecrude material was purified by preparative reverse phase HPLC (Gemini,15 to 50% ACN/H₂O+0.1% TFA) to yield methyl(R)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(95 mg, 47%). LCMS-ESI⁺: calculated for C₄₇H₄₈N₈O₆S: 853.00. observed[M+1]⁺: 853.85.

Example BC

methyl(R)-2-((S)-2-(5-(7-(2-((S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

Methyl(R)-2-((S)-2-(5-(7-(2-((S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)dibenzo[b,d]thiophen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate:This compound was made in an analogous manner to Example BB,substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amidecoupling. LCMS-ESI⁺: calculated for C₄₇H₄₈N₈O₇S: 869.00. observed[M+1]⁺: 869.92.

Example BD

2,7-dibromo-9-(propan-2-ylidene)-9H-fluorene

To a mixture of solid 2,7-dibromo-9H-fluorene (1 g, 3.1 mmol) and solidpotassium hydroxide (freshly ground, 530 mg, 9.4 mmol) was added acetone(15 mL). The reaction immediately turns dark. After 3 hours the reactionwas diluted with ethyl acetate. The organics were washed with water andbrine, dried (MgSO₄) and concentrated to a dark blue-green oil. This oilwas dissolved in dichloromethane (10 mL) and formic acid (˜10 drops) wasadded until the solution was bright orange. After concentration, theresulting residue was purified by flash column chromatography to yield2,7-dibromo-9-(propan-2-ylidene)-9H-fluorene (145 mg, 13%) as an orangesolid.

2,2′-(9-(propan-2-ylidene)-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)

A solution of 2,7-dibromo-9-(propan-2-ylidene)-9H-fluorene (145 mg, 0.40mmol), bis(pinacolato)diboron (305 mg, 1.2 mmol) and potassium acetate(235 mg, 2.4 mmol) in 2:1 dioxane:dimethylformamide (4 mL) was degassedfor fifteen minutes. To this solution was added PdCl₂(dppf) (30 mg, 0.04mmol) and the reaction was heated to 85° C. for 2 hours. The mixture wascooled to room temperature, diluted with ethyl acetate and filteredthrough Celite. The filtrate was washed with water and brine, dried(MgSO₄) and concentrated. The resulting residue was diluted withdichloromethane (10 mL) and concentrated. Solids precipitatedimmediately upon addition of methanol (10 mL) to the crude residue. Thismixture was stirred for 30 minutes and then filtered to yield2,2′-(9-(propan-2-ylidene)-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)(90 mg, 49%) as a grey solid. LCMS-ESI⁺: calculated for C₂₈H₃₆B₂O₄:458.21. observed [M+1]⁺: 459.14.

tert-Butyl2,2′-(5,5′-(9-(propan-2-ylidene)-9H-fluorene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

A mixture of2,2′-(9-(propan-2-ylidene)-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)(90 mg, 0.20 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (155 mg, 0.50mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol),PdCl₂(dppf) (15 mg, 0.02 mmol), 2M aqueous potassium carbonate (0.60 mL,1.2 mmol), dimethoxyethane (1.7 mL) and dimethylformamide (0.3 mL) wasdegassed with argon for 15 minutes. The reaction was then heated to 85°C. for 2 hours. Upon completion, the reaction was cooled to roomtemperature, diluted with ethyl acetate and filtered through Celite. Thefiltrate was washed with water and brine, dried (MgSO₄) andconcentrated. The resulting crude material was purified by flash columnchromatography to yield tert-butyl2,2′-(5,5′-(9-(propan-2-ylidene)-9H-fluorene-2,7-diyl)bis(H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(70 mg, 53%). LCMS-ESI⁺: calculated for C₄₀H₄₈N₆O₄: 676.37. observed[M+1]⁺: 677.19.

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(9-(propan-2-ylidene)-9H-fluorene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

A solution of tert-butyl2,2′-(5,5′-(9-(propan-2-ylidene)-9H-fluorene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(70 mg, 0.10 mmol), concentrated HCl (0.5 mL) and ethanol (3 mL) washeated to 60° C. for one hour. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offthree more times, until the crude material was a powder. The crude aminewas dissolved in dimethylformamide (1.2 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (49 mg, 0.28 mmol),HATU (93 mg, 0.24 mmol) and diisopropylethylamine (0.12 mL, 0.67 mmol).The reaction was stirred at room temperature for one hour. Uponcompletion, the reaction was diluted with ethyl acetate and the organiclayer was washed with water and brine. The combined aqueous washingswere extracted three times with ethyl acetate, and the combined organiclayers were dried (MgSO₄) and concentrated. The crude material waspurified by preparative reverse phase HPLC (Gemini, 15 to 50%ACN/H₂O+0.1% TFA) to yield dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(9-(propan-2-ylidene)-9H-fluorene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(51 mg, 62%). LCMS-ESI⁺: calculated for C₄₄H₅₄N₈O₆: 790.95. observed[M+1]⁺: 791.71.

Example BE

6,11-Dibromodibenzo[f,h]quinoxaline

A mixture of 2,7-dibromophenanthrene-9,10-dione (1.0 g, 2.7 mmol),ethylenediamine (1.8 mL, 26.9 mmol) and ethanol (20 mL) was heated to85° C. After 3 hours, the reaction was cooled to room temperature andthe solids were filtered and thoroughly washed methanol to yield6,11-dibromodibenzo[f,h]quinoxaline (360 mg, 34%).

6,11-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[f,h]quinoxaline

A solution of 6,11-dibromodibenzo[f,h]quinoxaline (360 mg, 0.92 mmol),bis(pinacolato)diboron (700 mg, 2.8 mmol) and potassium acetate (545 mg,5.5 mmol) in 2:1 dioxane:dimethylformamide (9.2 mL) was degassed forfifteen minutes. To this solution was added PdCl₂(dppf) (70 mg, 0.09mmol) and the reaction was heated to 85° C. for 6 hours. The mixture wascooled to room temperature, diluted with ethyl acetate and filteredthrough Celite. The filtrate was washed with water and brine, dried(MgSO₄) and concentrated. The resulting residue was diluted withdichloromethane (10 mL) and concentrated. Solids precipitatedimmediately upon addition of methanol (10 mL) to the crude residue. Thismixture was stirred for 30 minutes, filtered and thoroughly rinsed withmethanol to yield6,11-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[f,h]quinoxaline(270 mg, 61%) as a grey solid.

(2S,2′S)-tert-butyl2,2′-(5,5′-(dibenzo[f,h]quinoxaline-6,11-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

A mixture of6,11-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[f,h]quinoxaline(270 mg, 0.55 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (435 mg, 1.40mmol), tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.06 mmol),PdCl₂(dppf) (40 mg, 0.06 mmol), 2M aqueous potassium carbonate (1.65 mL,3.3 mmol), dimethoxyethane (4.6 mL) and dimethylformamide (0.9 mL) wasdegassed with argon for 15 minutes. The reaction was then heated to 85°C. for 16 hours. Upon completion, the reaction was cooled to roomtemperature, diluted with ethyl acetate and filtered through Celite. Thefiltrate was washed with water and brine, dried (MgSO₄) andconcentrated. The resulting crude material was purified by flash columnchromatography to (2S,2′S)-tert-butyl2,2′-(5,5′-(dibenzo[f,h]quinoxaline-6,11-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(150 mg, 39%). LCMS-ESI⁺: calculated for C₄₀H₄₄N₈O₄: 700.35. observed[M+1]⁺: 701.21.

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(dibenzo[f,h]quinoxaline-6,11-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

A solution (2S,2′S)-tert-butyl2,2′-(5,5′-(dibenzo[f,h]quinoxaline-6,11-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(150 mg, 0.21 mmol), concentrated HCl (1.0 mL) and ethanol (6 mL) washeated to 60° C. for one hour. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offthree more times, until the crude material was a powder. The crude aminewas dissolved in dimethylformamide (2.1 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (95 mg, 0.54 mmol),HATU (190 mg, 0.49 mmol) and diisopropylethylamine (0.225 mL, 1.3 mmol).The reaction was stirred at room temperature for one hour. Uponcompletion, the reaction was diluted with ethyl acetate and the organiclayer was washed with water and brine. The combined aqueous washingswere extracted three times with ethyl acetate, and the combined organiclayers were dried (MgSO₄) and concentrated. The crude material waspurified by preparative reverse phase HPLC (Gemini, 15 to 50%ACN/H₂O+0.1% TFA) to yield dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(dibenzo[f,h]quinoxaline-6,11-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(101 mg, 58%). LCMS-ESI⁺: calculated for C₄₄H₅₀N₁₀O₆: 814.93. observed[M+1]⁺: 815.83.

Example BF

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(dibenzo[a,c]phenazine-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(dibenzo[a,c]phenazine-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate:This compound was made in an analogous manner to(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(dibenzo[h]quinoxaline-6,11-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate,substituting 1,2-phenylenediamine for ethylenediamine in the first step.LCMS-ESI⁺: calculated for C₄₈H₅₂N₁₀O₆: 864.99. observed [M+1]⁺: 865.92.

Example BG

2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-cyclopenta[def]phenanthren-4-one

A solution of 2,6-dibromo-4H-cyclopenta[def]phenanthren-4-one (425 mg,1.2 mmol), bis(pinacolato)diboron (895 mg, 3.5 mmol) and potassiumacetate (695 mg, 7.0 mmol) in 2:1 dioxane:dimethylformamide (12 mL) wasdegassed for fifteen minutes. To this solution was added PdCl₂(dppf) (86mg, 0.12 mmol) and the reaction was heated to 85° C. for 2 hours. Themixture was cooled to room temperature, diluted with ethyl acetate andfiltered through Celite. The filtrate was washed with water and brine,dried (MgSO₄) and concentrated. Solids precipitated immediately uponaddition of methanol (30 mL) to the crude residue. This mixture wasstirred for one hour, filtered and thoroughly rinsed with methanol toyield2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-cyclopenta[def]phenanthren-4-one(260 mg, 49%) as a grey solid.

(2S,2′S)-tert-butyl2,2′-(5,5′-(4-oxo-4H-cyclopenta[def]phenanthrene-2,6-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

A mixture of2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-cyclopenta[def]phenanthren-4-one(260 mg, 0.57 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (455 mg, 1.44mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol),PdCl₂(dppf) (45 mg, 0.06 mmol), 2M aqueous potassium carbonate (1.75 mL,3.5 mmol), dimethoxyethane (5.0 mL) and dimethylformamide (1.0 mL) wasdegassed with argon for 15 minutes. The reaction was then heated to 85°C. for 3 hours. Upon completion, the reaction was cooled to roomtemperature, diluted with ethyl acetate and filtered through Celite. Thefiltrate was washed with water and brine, dried (MgSO₄) andconcentrated. The resulting crude material was purified by flash columnchromatography to (2S,2′S)-tert-butyl2,2′-(5,5′-(4-oxo-4H-cyclopenta[def]phenanthrene-2,6-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(148 mg, 38%). LCMS-ESI⁺: calculated for C₃₉H₄₂N₆O₅: 674.32. observed[M+1]⁺: 675.09.

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(4-oxo-4H-cyclopenta[def]phenanthrene-2,6-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

A solution (2S,2′S)-tert-butyl2,2′-(5,5′-(4-oxo-4H-cyclopenta[def]phenanthrene-2,6-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(148 mg, 0.22 mmol), concentrated HCl (1.0 mL) and ethanol (6 mL) washeated to 60° C. for one hour. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offthree more times, until the crude material was a powder. The crude aminewas dissolved in dimethylformamide (2.2 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (95 mg, 0.54 mmol),HATU (190 mg, 0.49 mmol) and diisopropylethylamine (0.250 mL, 1.4 mmol).The reaction was stirred at room temperature for two hours. Uponcompletion, the reaction was diluted with ethyl acetate and the organiclayer was washed with water and brine. The combined aqueous washingswere extracted three times with ethyl acetate, and the combined organiclayers were dried (MgSO₄), filtered through a freebasing column(Stratospheres™ PL-HCO₃MP SPE, Part #: PL3540-C603) and concentrated.The crude material was purified by preparative reverse phase HPLC(Gemini, 15 to 50% ACN/H₂O+0.1% TFA) to yield dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(4-oxo-4H-cyclopenta[def]phenanthrene-2,6-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(92 mg, 53%). LCMS-ESI⁺: calculated for C₄₃H₄₈N₈O₇: 788.89. observed[M+1]⁺: 789.67.

Example BH

2,7-dichlorophenanthrene-9-carbonitrile

To a microwave vial was added 4-chloro-2-formylphenylboronic acid (480mg, 2.6 mmol), 2-(2-bromo-5-chlorophenyl)acetonitrile (500 mg, 2 mmol),tetrakis(triphenyl phosphine)palladium (0) (100 mg, 0.085 mmol) andcesium carbonate (2.12g, 6.5 mmol) sequentially. The mixture wassuspended in toluene (10 mL) and methanol (5 mL). Then the reaction vialwas sealed and place in a microwave reactor and irradiated at 150° C.for 10 minutes. The reaction was cooled to room temperature, dilutedwith ethyl acetate, and filtered through a short celite pad. Thesolution was concentrated. The crude residue was purified by flashchromatography to yield 2,7-dichlorophenanthrene-9-carbonitrile (110 mg,19%)

2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenanthrene-9-carbonitrile

A degassed mixture of 2,7-dichlorophenanthrene-9-carbonitrile (105 mg,0.39 mmol), bis(pinacolato)diboron (294 mg, 1.15 mmol), potassiumacetate (227 mg, 2.3 mmol), tris(dibenzylideneacetone)palladium (28 mg,0.03 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (29 mg, 0.06mmol) in 1,4-dioxane (1.0 mL) was heated to 85° C. for 3 hours, cooledto room temperature and diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was triturated with methanol, the precipitate was filtered offto yield 2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenanthrene-9-carbonitrile (82 mg, 47%)

(2S,2′S)-tert-butyl2,2′-(5,5′-(9-cyanophenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

To a solution of2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenanthrene-9-carbonitrile(147 mg, 0.32 mmol), (S)-tert-butyl2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (255 mg, 0.8mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.02 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (24 mg, 0.03mmol) in a mixture of 1,2-dimethoxyethane (5.0 mL) and dimethylformamide(1 mL) was added a solution of potassium carbonate (2M in water, 0.5 mL,0.96 mmol). The resulting mixture was degassed and then heated to 85° C.under argon for 18 hours. After cooling to room temperature, thereaction was diluted with ethyl acetate. The organics were washed withwater and brine, dried (Na₂SO₄), and concentrated. The crude residue waspurified by flash chromatography to yield (2S,2′S)-tert-butyl2,2′-(5,5′-(9-cyanophenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(119 mg, 55%)

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(9-cyanophenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

A solution of (2S,2′S)-tert-butyl2,2′-(5,5′-(9-cyanophenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(119 mg, 0.18 mmol), ethanol (6 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of2-methoxycarbonylamino-3-methylbutyric acid (77 mg, 0.44 mmol) and HATU(154 mg, 0.41 mmol) in DMF (3 mL). To the resulting solution was addeddiisopropylethylamine (190 μL, 1.1 mmol). After stirring for 18 hours atroom temperature, the reaction was diluted with ethyl acetate, washedwith water and brine, dried (Na₂SO₄), concentrated and purified bypreparative reverse phase HPLC (Gemini, 15 to 50% ACN/H₂O+0.1% TFA). Theproduct fractions were lyophilized to give Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(9-cyanophenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(55 mg, 39%). LCMS-ESI⁺: calculated for C₄₃H₄₉N₉O₆: 787.93. observed[M+1]⁺: 788.75.

Example BI

2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenanthrene

A degassed mixture of 2,7-dibromophenanthrene (1.21 g, 3.57 mmol),bis(pinacolato)diboron (2.72 g, 10.7 mmol), potassium acetate (2.10 g,21.4 mmol), tris(dibenzylideneacetone)palladium (262 mg, 0.28 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (272 mg,0.57 mmol) in 1,4-dioxane (1.0 mL) was heated to 85° C. for 3 hours,cooled to room temperature and diluted with ethyl acetate. The organicswere washed with water and brine, dried (Na₂SO₄), and concentrated. Thecrude residue was triturated with methanol, the precipitate was filteredoff to yield 2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenanthrene (1.21 g, 77%)

(2S,2′S)-tert-butyl2,2′-(5,5′-(phenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

To a solution of 2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenanthrene (250 mg, 0.58 mmol), (S)-tert-butyl2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (459 mg, 1.45mmol), tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.03 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (43 mg, 0.06mmol) in a mixture of 1,2-dimethoxyethane (5.0 mL) and dimethylformamide(1 mL) was added a solution of potassium carbonate (2M in water, 1.8 mL,3.4 mmol). The resulting mixture was degassed and then heated to 85° C.under argon for 18 hours. After cooling to room temperature, thereaction was diluted with ethyl acetate. The organics were washed withwater and brine, dried (Na₂SO₄), and concentrated. The crude residue waspurified by flash chromatography to yield (2S,2′S)-tert-butyl2,2′-(5,5′-(phenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(237 mg, 38%)

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(phenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

A solution of (2S,2′S)-tert-butyl2,2′-(5,5′-(phenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(235 mg, 0.36 mmol), ethanol (6 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of2-methoxycarbonylamino-3-methylbutyric acid (144 mg, 0.82 mmol) and HATU(287 mg, 0.75 mmol) in DMF (3 mL). To the resulting solution was addeddiisopropylethylamine (340 μL, 1.97 mmol). After stirring for 18 hoursat room temperature, the reaction was diluted with ethyl acetate, washedwith water and brine, dried (Na₂SO₄), concentrated and purified bypreparative reverse phase HPLC (Gemini, 15 to 50% ACN/H₂O+0.1% TFA). Theproduct fractions were lyophilized to give dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(phenanthrene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(122 mg, 44%). LCMS-ESI⁺: calculated for C₄₂H₅₀N₈O₆: 762.92. observed[M+1]⁺: 763.47.

Example BJ

2-bromo-1-(7-bromo-9,1-dihydrophenanthren-2-yl)ethanone

A degassed mixture of 2,7-dibromo-9,10-dihydrophenanthrene (3.5 g, 10.35mmol), tributyl-(1-ethoxyvinyl)tin (3.8 mL, 11.4 mmol),tetrakis(triphenylphosphine)palladium(0) (598 mg, 0.52 mmol) anddichloro[1,1′-bis(diphenyl-phosphino) ferrocene]palladium(II) (378 mg,0.52 mmol) in 1,4-dioxane (1.0 mL) was heated to 85° C. for 18 hours,cooled to room temperature and N-bromosuccinimide (2.21 g, 12.42 mmol)and water (25 mL) were added. The reaction mixture was stirred at roomtemperature for 2 hours, diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield2-bromo-1-(7-bromo-9,10-dihydrophenanthren-2-yl)ethanone (635 mg, 16%).

(1R,3S,4S)-tert-butyl3-(5-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a solution of(4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (443 mg, 1.83 mmol) and2-bromo-1-(7-bromo-9,10-dihydrophenanthren-2-yl)ethanone (635 mg, 1.67mmol) in acetonitrile (7 mL) was added diisopropylethylamine (0.6 mL,3.34 mmol). The reaction was stirred at room temperature for 16 hoursand was then diluted with ethyl acetate. The organics were washed withwater and brine, dried (MgSO₄) and concentrated. The resulting cruderesidue was purified by flash chromatography to yield(1R,3S,4S)-tert-butyl3-(5-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(670 mg, 74%).

To a solution of (1R,3S,4S)-tert-butyl3-(5-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(665 mg, 1.23 mmol) in a mixture of toluene (1.8 mL) and2-methoxyethanol (0.1 mL) was added ammonium acetate (474 mg, 6.15mmol). The reaction mixture was heated to 90° C. for 18 hours, cooled toroom temperature and diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield(1R,3S,4S)-tert-butyl3-(5-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(373 mg, 58%). LCMS-ESI⁺: calculated for C₂₈H₃₀BrN₃O₂: 520.47. observed[M+1]⁺: 520.97.

(1R,3S,4S)-tert-butyl3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

A degassed mixture of3-(5-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(369 mg, 0.71 mmol), bis(pinacolato)diboron (270 mg, 1.06 mmol),potassium acetate (209 mg, 2.13 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (26 mg,0.035 mmol) in 1,4-dioxane (5 mL) was heated to 90° C. for 3 hours,cooled to room temperature and diluted with ethyl acetate. The organicswere washed with water and brine, dried (Na₂SO₄), and concentrated. Thecrude (1R,3S,4S)-tert-butyl-3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenan-thren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylatewas used without further purification. LCMS-ESI⁺: calculated forC₃₄H₄₂BN₃O₄: 567.54. observed [M+1]⁺: 568.09.

methyl(S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate

A solution of(1R,3S,4S)-tert-butyl-3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(˜0.69 mmol), ethanol (6 mL) and concentrated HCl (2 mL) was heated to60° C. for 1.5 hours. The reaction was concentrated and the crudematerial dissolved in DCM (10 mL). This solution was concentrated and tothis material was added a solution of2-methoxycarbonylamino-3-methylbutyric acid (162 mg, 0.9 mmol) and HATU(397 mg, 1.04 mmol) in DMF (5 mL). To the resulting solution was addeddiisopropylethylamine (360 μL, 2.08 mmol). After stirring for 18 hoursat room temperature, the reaction was diluted with ethyl acetate, washedwith water and brine, dried (Na₂SO₄), concentrated and the crude methyl(S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamatewas used without further purification. LCMS-ESI⁺: calculated forC₃₆H₄₅BN₄O₅: 624.59. observed [M+1]⁺: 625.35.

S)-tert-butyl-2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicy-clo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrro-lidine-1-carboxylate

To a solution of methyl (S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate(˜0.67 mmol), (S)-tert-butyl2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (266 mg, 0.84mmol), tetrakis(triphenylphosphine) palladium(0) (23 mg, 0.02 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (30 mg, 0.04mmol) in a mixture of 1,2-dimethoxyethane (10.0 mL) anddimethylformamide (2 mL) was added a solution of potassium carbonate (2Min water, 1.0 mL, 2.0 mmol). The resulting mixture was degassed and thenheated to 85° C. under argon for 18 hours. After cooling to roomtemperature, the reaction was diluted with ethyl acetate. The organicswere washed with water and brine, dried (Na₂SO₄), and concentrated. Thecrude residue was purified by flash chromatography to yieldS)-tert-butyl 2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(182 mg, 56%)

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((3R)-3-methoxy-2-(methoxycarbonylamino)buta-noyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

A solution of S)-tert-butyl2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(86 mg, 0.12 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of(3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (29 mg, 0.15 mmol)and HATU (67 mg, 0.18 mmol) in DMF (1.5 mL). To the resulting solutionwas added diisopropylethylamine (600 μL, 3.5 mmol). After stirring for18 hours at room temperature, the reaction was diluted with ethylacetate, washed with water and brine, dried (Na₂SO₄), concentrated andpurified by preparative reverse phase HPLC (Gemini, 15 to 50%ACN/H₂O+0.1% TFA). The product fractions were lyophilized to give Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((3R)-3-methoxy-2-(methoxycarbonylamino)buta-noyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (39 mg, 41%). LCMS-ESI⁺: calculatedfor C₄₄H₅₄N₈O₇: 806.97. observed [M+1]⁺: 807.74.

Example BK

methyl(S)-3-methyl-1-oxo-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl) butan-2-ylcarbamate

A solution S)-tert-butyl2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(92 mg, 0.13 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (35mg, 0.16 mmol) and HATU (71 mg, 0.19 mmol) in DMF (1.5 mL). To theresulting solution was added diisopropylethylamine (700 μL, 3.8 mmol).After stirring for 18 hours at room temperature, the reaction wasdiluted with ethyl acetate, washed with water and brine, dried (Na₂SO₄),concentrated and purified by preparative reverse phase HPLC (Gemini, 10to 1% TFA/H₂O+1% TFA/CH₃CN). The product fractions were lyophilized togive methyl(S)-3-methyl-1-oxo-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrro-lidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(36 mg, 34%). LCMS-ESI⁺: calculated for C₄₆H₅₆N₈O₇: 833.01. observed[M+1]⁺: 833.58.

Example BL

3-(2-Amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

To a solution of 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid2-tert-butyl ester (0.327 g, 1.36 mmol, 1 eq.),4-Bromo-benzene-1,2-diamine (0.507 g, 2.71 mmol, 2 eq.) and4-methylmorpholine (0.299 mL, 2 eq.) in 10 mL DMF was added HATU(0.543g, 1.05 eq.). The reaction mixture was stirred at room temperaturefor 1 hour then concentrated down. The reaction mixture was diluted withethyl acetate and washed with diluted NaHCO3 aqueous solution and brine.The organic layer was concentrated down and purified by flash columnchromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give amixture of regioisomer3-(2-Amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester.

3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

The above mixture of regioisomer3-(2-Amino-4-bromo-phenylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester was dissolved in ethanol and heated to 130° C. insealed tube overnight and continue heating at 170° C. for 3 days. LC-MSshowed desired product and Boc cleaved product (about 1:1 ratio). Themixture was concentrated down and dissolved DCM. Di-tert-butyldicarbonate (0.6 eq.) was added and reaction was stirred overnight atroom temperature. The reaction mixture was concentrated down andpurified by flash column chromatography (silica gel, 20 to 80% ethylacetate/hexane) to give3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.383 g, 72%) as an orange foam.

8-chloro-3-methoxy-6H-benzo[c]chromene

To a solution of 3-methoxyphenol (0.84 mL, 7.3 mmol) and1-bromo-2-(bromomethyl)-4-chlorobenzene (2 g, 7 mmol) in DMF (70 mL) wasadded potassium carbonate (1.94 g, 14 mmol). The reaction mixture wasstirred at room temperature for 16 hours, then poured into water (500mL) extracted into ethyl acetate. The organics were washed with waterand brine, dried (Na₂SO₄), and concentrated. The crude residue waspurified by flash chromatography to yield1-bromo-4-chloro-2-((3-methoxyphenoxy)methyl) benzene (2 g, 87%)

To a degassed mixture of potassium carbonate (1.27 g, 9 mmol),palladium(II)trimethyl acetate (47 mg, 0.15 mmol), tris(p-fluorophenyl)phosphine (48 mg, 0.15 mmol) and trimethylacetic acid(93 mg, 0.9 mmol) was added1-bromo-4-chloro-2-((3-methoxyphenoxy)methyl)benzene (1 g, 3 mmol) inN,N-dimethylacetamide (14 mL). The reaction was heated to 60° C. underargon for 18 hours. Upon completion, the reaction mixture was cooled toroom temperature. The products were loaded directly onto a silica gelpacked column and eluted using Hexanes/ethyl acetate to yield8-chloro-3-methoxy-6H-benzo[c]chromene (739 mg, 98%)

8-chloro-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate

8-chloro-3-methoxy-6H-benzo[c]chromene (670 mg, 2.7 mmol) and pyridiniumhydrochloride (3.16 g, 27.3 mmol) were heated to 185° C. for 2.5 hours.After cooling to room temperature, the reaction was diluted with waterextracted into ethyl acetate. The organics were washed with water andbrine, dried (Na₂SO₄), and concentrated. The crude residue was purifiedby flash chromatography to yield 8-chloro-6H-benzo[c]chromen-3-ol (523mg, 82%)

To 8-chloro-6H-benzo[c]chromen-3-ol (798 mg, 3.4 mmol) indichloromethane (25 mL) at 0° C. was added trifluoromethanesulfonicanhydride (0.36 mL, 4.5 mmol) dropwise, the mixture was stirred for 2hours, then poured into 1.0M HCl solution (50 mL) extracted into ethylacetate. The organics were washed with water and brine, dried (Na₂SO₄),and concentrated. The crude residue was purified by flash chromatographyto yield 8-chloro-6H-benzo[c]chromen-3-yl trifluorome-thanesulfonate(1.16 g, 94%)

2-(8-chloro-6H-benzo[c]chromen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A degassed mixture of -chloro-6H-benzo[c]chromen-3-yltrifluorome-thanesulfonate (744 mg, 2 mmol), bis(pinacolato)diboron (785mg, 3 mmol), potassium acetate (607 mg, 6.2 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (75 mg,0.103 mmol) in 1,4-dioxane (12 mL) was heated to 90° C. for 3 hours,cooled to room temperature and diluted with ethyl acetate. The organicswere washed with water and brine, dried (Na₂SO₄), and concentrated. Thecrude residue was purified by flash chromatography to yield2-(8-chloro-6H-benzo[c]chromen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(699 mg, 71%)

(S)-tert-butyl2-(5-(8-chloro-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of2-(8-chloro-6H-benzo[c]chromen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(773 mg, 2.24 mmol), (S)-tert-butyl2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (886 mg, 2.8mmol), tetrakis(triphenylphosphine) palladium(0) (65 mg, 0.05 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (82 mg, 0.11mmol) in a mixture of 1,2-dimethoxyethane (10.0 mL) anddimethylformamide (2 mL) was added a solution of potassium carbonate (2Min water, 3.5 mL, 7.0 mmol). The resulting mixture was degassed and thenheated to 85° C. under argon for 18 hours. After cooling to roomtemperature, the reaction was diluted with ethyl acetate. The organicswere washed with water and brine, dried (Na₂SO₄), and concentrated. Thecrude residue was purified by flash chromatography to yield(S)-tert-butyl 2-(5-(8-chloro-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (617 mg, 50%). LCMS-ESI⁺: calculated forC₂₅H₂₆ClN₃O₃: 451.96. observed [M+1]⁺: 452.53.

(S)-tert-butyl2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A degassed mixture of (S)-tert-butyl2-(5-(8-chloro-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (615 mg, 1.8 mmol), bis(pinacolato)diboron(429 mg, 1.69 mmol), potassium acetate (332 mg, 3.38 mmol),tris(dibenzylideneacetone)palladium (52 mg, 0.06 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (54 mg, 0.11mmol) in 1,4-dioxane (6 mL) was heated to 90° C. for 5 hours, cooled toroom temperature and diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield S)-tert-butyl2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (675 mg, 69%). LCMS-ESI⁺: calculated forC₃₁H₃₈BN₃O₅: 543.48. observed [M+1]⁺: 544.04.

methyl3-methyl-1-oxo-1-((S)-2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

A solution of (S)-tert-butyl2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (670 mg, 1.23 mmol), ethanol (6 mL) andconcentrated HCl (2 mL) was heated to 60° C. for 1.5 hours. The reactionwas concentrated and the crude material dissolved in DCM (10 mL). Thissolution was concentrated and to this material was added a solution of2-methoxycarbonylamino-3-methylbutyric acid (268 mg, 1.6 mmol) and HATU(537 mg, 1.41 mmol) in DMF (6 mL). To the resulting solution was addeddiisopropylethylamine (640 μL, 3.68 mmol). After stirring for 18 hoursat room temperature, the reaction was diluted with ethyl acetate, washedwith water and brine, dried (Na₂SO₄), concentrated. The crude residuewas purified by flash chromatography to yield methyl3-methyl-1-oxo-1-((S)-2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(205 mg, 28%). LCMS-ESI⁺: calculated for C₃₃H₄₁BN₄O₆: 600.53. observed[M+1]⁺: 601.39.

(4S)-tert-butyl3-(6-(3-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-8-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a solution of methyl3-methyl-1-oxo-1-((S)-2-(5-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(196 mg, 0.32 mmol), (1R,3 S,4S)-tert-butyl3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(166 mg, 0.42 mmol), tetrakis(triphenylphosphine) palladium(0) (10 mg,0.01 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (12 mg, 0.02mmol) in a mixture of 1,2-dimethoxyethane (5 mL) and dimethylformamide(1 mL) was added a solution of potassium carbonate (2M in water, 0.51mL, 0.31 mmol). The resulting mixture was degassed and then heated to85° C. under argon for 18 hours. After cooling to room temperature, thereaction was diluted with ethyl acetate. The organics were washed withwater and brine, dried (Na₂SO₄), and concentrated. The crude residue waspurified by flash chromatography to yield S)-tert-butyl 4S)-tert-butyl3-(6-(3-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chro-men-8-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(215 mg, 85%) LCMS-ESI⁺: calculated for C₄₅H₅₁N₇O₆: 785.95. observed[M+1]⁺: 786.43.

methyl(1R)-2-((4S)-3-methyl-3-(6-(3-(2-((methoxycarbonylamino)-3-methylbutanoyl))-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-8-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamate

A solution yield S)-tert-butyl 4 S)-tert-butyl3-(6-(3-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-8-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(213 mg, 0.27 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1.5 hours. The reaction was concentrated and thecrude material dissolved in DCM (6 mL). This solution was concentratedand to this material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (73 mg, 0.35 mmol) andCOMU (132 mg, 0.31 mmol) in DMF (3 mL). To the resulting solution wasadded diisopropylethylamine (140 μL, 0.81 mmol). After stirring for 18hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give methyl(1R)-2-((4S)-3-methyl-3-(6-(3-(2-((methoxycarbonylamino)-3-methylbutanoyl))-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-8-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamate(34 mg, 14%). LCMS-ESI⁺: calculated for C₅₀H₅₂N₈O₇: 877.02; observed[M+1]⁺: 877.80.

Example BM

(1 S,31R)-tert-butyl3-(6-(8-chloro-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a solution of2-(8-chloro-6H-benzo[c]chromen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(750 mg, 2.18 mmol), (1R,3 S,4S)-tert-butyl3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(1.07 mg, 2.72 mmol), tetrakis(triphenylphosphine) palladium(O) (75 mg,0.07 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (96 mg, 0.13mmol) in a mixture of 1,2-dimethoxyethane (10 mL) and dimethylformamide(2 mL) was added a solution of potassium carbonate (2M in water, 3.5 mL,6.53 mmol). The resulting mixture was degassed and then heated to 85° C.under argon for 18 hours. After cooling to room temperature, thereaction was diluted with ethyl acetate. The organics were washed withwater and brine, dried (Na₂SO₄), and concentrated. The crude residue waspurified by flash chromatography to yield (1S,3R)-tert-butyl3-(6-(8-chloro-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(285 mg, 25%) LCMS-ESI⁺: calculated for C₃₁H₃₀ClN₃O₃: 528.06; observed[M+1]⁺: 528.36.

(1S,3R)-tert-butyl3-(6-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

A degassed mixture of (1S,3R)-tert-butyl3-(6-(8-chloro-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(282 mg, 0.53 mmol), bis(pinacolato)diboron (202 mg, 0.8 mmol),potassium acetate (156 mg, 1.6 mmol),tris(dibenzylideneacetone)palladium (24 mg, 0.03 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (25 mg, 0.05mmol) in 1,4-dioxane (5 mL) was heated to 90° C. for 2.5 hours, cooledto room temperature and diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield (1S,3R)-tert-butyl3-(6-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabi-cyclo[2.2.1]heptane-2-carboxylate(278 mg, 84%) LCMS-ESI⁺: calculated for C₃₇H₄₂BN₃O₅: 619.58; observed[M+1]⁺: 620.14.

(1S,3R)-tert-butyl3-(6-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a solution of (1S,3R)-tert-butyl3-(6-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabi-cyclo[2.2.1]heptane-2-carboxylate(275 mg, 0.44 mmol), methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(221 mg, 0.55 mmol), tetrakis (triphenylphosphine) palladium(0) (20 mg,0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (26 mg, 0.04 mmol) in a mixture of1,2-dimethoxyethane (5.0 mL) and dimethylformamide (1 mL) was added asolution of potassium carbonate (2M in water, 0.7 mL, 1.3 mmol). Theresulting mixture was degassed and then heated to 85° C. under argon for18 hours. After cooling to room temperature, the reaction was dilutedwith ethyl acetate. The organics were washed with water and brine, dried(Na₂SO₄), and concentrated. The crude residue was purified by flashchromatography to yield (1S,3R)-tert-butyl3-(6-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methyl-butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(70 mg, 20%). LCMS-ESI⁺: calculated for C₄₅H₅₁N₇O₆: 785.95. observed[M+1]⁺: 786.85.

methyl(1S)-2-oxo-1-phenyl-2-((1S,3R)-3-(6-(8-(2-((methoxycarbonylamino)-3-methylbutanoyl)(S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)ethylcarbamate

A solution yield (1S,3R)-tert-butyl3-(6-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methyl-butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(70 mg, 0.08 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1.5 hours. The reaction was concentrated and thecrude material dissolved in DCM (6 mL). This solution was concentratedand to this material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (48 mg, 0.23 mmol) andCOMU (88 mg, 0.20 mmol) in DMF (3 mL). To the resulting solution wasadded diisopropylethylamine (0.54 mmol). After stirring for 18 hours atroom temperature, the reaction was diluted with ethyl acetate, washedwith water and brine, dried (Na₂SO₄), concentrated and purified bypreparative reverse phase HPLC (Gemini, 15 to 50% ACN/H₂O+0.1% TFA). Theproduct fractions were lyophilized to give methyl(1S)-2-oxo-1-phenyl-2-((1S,3R)-3-(6-(8-(2-((methoxycarbonylamino)-3-methylbutanoyl)(S)-pyrro-lidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)ethylcarbamate(4.8 mg, 6%). LCMS-ESI⁺: calculated for C₅₀H₅₂N₈O₇: 877.02; observed[M+1]⁺: 877.72.

Example BN

(S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatewas prepared following the procedure for2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (Example EQ), substituting4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester forPyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.

(S)-tert-Butyl2-(5-(6-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Dimethyl sulfide (164 μL, 2.23 mmol) was added dropwise to a solution ofN-chlorosuccinimide (238 mg, 2.12 mmol) in dichloromethane (10 mL) at 0°C. After 15 minutes the mixture was cooled to −15° C. (ice-salt bath). Asolution of (S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(809 mg, 1.06 mmol) in dichloromethane (5 mL) was added dropwise. Thetemperature was not allowed to go above −10° C. After 2 hours a solutionof triethylamine (316 μL, 2.23 mmol) in dichloromethane (2 mL) was addeddropwise and the mixture was allowed to warm to room temperature atwhich point the reaction was complete. The mixture was washed withsaturated ammonium chloride (3×10 mL), dried over sodium sulfate andfiltered. The solvent was removed under reduced pressure and the residuewas subjected to flash chromatography with eluent of (10% methanol inethyl acetate) and hexane. The product containing fractions werecombined and the solvent was removed under reduced pressure to yield(S)-tert-butyl2-(5-(6-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(734 mg, 0.96 mmol, 90%).

[1-(2-{4-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

A solution of (S)-tert-butyl2-(5-(6-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(367 mg, 0.49 mmol) in dichloromethane (10 mL) was treated with asolution of hydrogen chloride in dioxane (4 N, 10 mL). After 1 hour thesolvent was removed under reduced pressure and placed on high vacuum for30 min. The solid was taken up in N,N-dimethylformamide (2 mL) andN-methylmorpholine (136 μL, 1.23 mmol) was added to the solution. In aseparate vessel, COMU (232 mg, 0.541 mmol), and N-methylmorpholine (136μL, 1.23 mmol) were added to a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (113 mg, 0.541 mmol) indichloromethane (2 mL). This was stirred for 5 minutes and bothsolutions were combined. After 15 minutes the mixture was neutralizedwith trifluroacetic acid and the solvent was removed under reducedpressure. The resulting DMF solution was subject to reverse phase HPLCwith eluant of acetonitrile eluent of 0.1% TFA in water and 0.1% TFA inacetonitrile. The product containing fractions were combined and thesolvent was removed by lyopholization to provide[1-(2-{4-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (121 mg, 0.14 mmol, 28%). C₄₇H₄₈N₈O₇ calculated 836.3observed [M+1]⁺ 837.4; rt=1.71 min.

Example BO

[1-(2-{4-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-oxo-pyrrolidin-2-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{4-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-oxo-pyrrolidin-2-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example BN substituting(2S,4S)-tert-butyl4-hydroxy-2-(4-(6-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.C₄₇H₄₈N₈O₇ calculated 836.3 observed [M+1]⁺ 837.4; rt=1.68 min.

Example BP

[1-(2-{4-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{4-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example BN substituting(S)-tert-butyl2-(4-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.C₄₇H₄₈N₈O₇ calculated 836.3 observed [M+1]⁺ 837.5; rt=1.70 min.

Example BQ

[1-(2-{4-[4-(6-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{4-[4-(6-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example BN substituting(R)-2-(dimethylamino)-2-phenylacetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid. C₄₇H₅₀N₈O₅ calculated806.4 observed [M+1]⁺ 807.4; rt=1.51 min.

Example BR

[1-(2-{4-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{4-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example BN substituting(R)-2-(dimethylamino)-2-phenylacetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid and (S)-tert-butyl2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.C₄₇H₅₀N₈O₅ calculated 806.4 observed [M+1]⁺ 807.3; rt=1.55 min.

Example BS

[1-(2-{4-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-oxo-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{4-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-oxo-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example BN substituting(R)-2-(dimethylamino)-2-phenylacetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid and (2S,4S)-tert-butyl4-hydroxy-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.C₄₇H₅₀N₈O₅ calculated 806.4 observed [M+1]⁺ 807.3; rt=1.53 min.

Example BT

(E)-1-(4-Bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one

A solution of 1-tert-Butoxy-N,N,N′,N′-tetramethylmethanediamine (19.2mL, 93.0 mmol) and solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (10g, 46.5 mmol) in toluene (100 mL) was heated at 35° C. for 16 hours andat 80° C. for 1 hour. The solvent was removed under reduced pressure.The resulting solid was subjected to flash chromatography with eluant ofdichloromethane. The product containing fractions were combined and thesolvent was removed under reduced pressure to provide(E)-1-(4-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one (10.4g, 38.5 mmol, 82%).

7-Bromo-4H-chromen-4-one

A solution of concentrated hydrochloric acid (30 mL) was added to asolution of(E)-1-(4-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one (10.4g, 38.5 mmol) in dichloromethane (250 mL). The mixture was heated atreflux for 30 minutes and cooled to room temperature. The aqueous phasewas extracted with dichloromethane (20 mL). The combined organic phaseswere washed with saturated sodium bicarbonate (50 mL), dried over sodiumsulfate and filtered. The solvent was removed under reduced pressure toyield 7-bromo-4H-chromen-4-one (8.7 g, 38.5 mol, 100%).

7-Bromochroman-4-one

A solution of diisobutylaluminum hydride in heptane (1.0 M, 60 mL, 60.0mmol) was added dropwise to a solution of 7-bromo-4H-chromen-4-one (4.5g, 20.0 mmol) in tetrahydrofuran at −78° C. under an atmosphere of argonover a period of 30 minutes. After 30 minutes the reaction was quenchedwith a mixture of silica gel (10 g), and water (10 mL). The mixture wasallowed to warm to room temperature and was filter through celite andthe tetrahydrofuran was removed under reduced pressure. The residue wastaken up in chloroform (100 mL) and washed with sodium hydroxide (1N, 25mL) and dried over sodium sulfate. The mixture was filtered and thesolvent was removed under reduced pressure. The residue was subjected toflash chromatography with eluant of dichloromethane. The productcontaining fractions were combined and the solvent was removed underreduced pressure to provide 7-bromochroman-4-one (3.57 g, 15.7 mmol,78%).

(E,Z)-7-Bromochroman-4-one oxime

A solution of sodium acetate (3.86 g, 47.2 mmol) in water (30 mL) wasadded to a solution of 7-bromochroman-4-one (3.57 g, 15.7 mmol), andhydroxylamine hydrochloride (1.64 g, 23.5 mmol) in ethanol (70 mL). Themixture was heated at reflux for 15 minutes. The mixture was cooled toroom temperature and diluted with water (50 mL). The resulting solid wasisolated by filtration, washed with water (50 mL) and azeotroped withtoluene to provide (E,Z)-7-bromochroman-4-one oxime (3.5 g, 14.5 mmol,92%).

(E,Z)-7-Bromochroman-4-one O-tosyl oxime

p-Toluenesulfonic anhydride (5.19 g, 15.9 mmol) was added to a solutionof E,Z)-7-bromochroman-4-one oxime (3.5 g, 14.5 mmol), and triethylamine(2.42 mL, 17.4 mmol) in dichloromethane (125 mL). After 1 hour themixture was washed with water (3×20 mL), brine (20 mL), dried oversodium sulfate and filtered. The solvent was removed under reducedpressure to provide (E,Z)-7-bromochroman-4-one O-tosyl oxime (5.5 g,14.3 mmol, 98%).

3-Amino-7-bromochroman-4-one hydrochloride

A solution of potassium ethoxide in ethanol (24% wt, 5.3 mL, 15.1 mmol)and then water (1 mL) were added to a solution of(E,Z)-7-bromochroman-4-one O-tosyl oxime (5.5 g, 14.3 mmol) in toluene(60 mL) and ethanol (30 mL). After 16 hours a solution of hydrogenchloride in dioxane (4 N, 20 mL) was added and the solvent was removedunder reduced pressure. The residue was stirred with diethyl ether (50mL). The resulting solid was isolated by filtration to provide3-amino-7-bromochroman-4-one hydrochloride (2.5 g, 8.9 mmol, 62%).

(2S)-tert-butyl2-(7-bromo-4-oxochroman-3-ylcarbamoyl)pyrrolidine-1-carboxylate

N-Methylmorpholine (2.14 mL, 19.4 mmol) was added to a mixture of(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.93 g, 8.98mmol) and 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (3.41 g, 8.98 mmol), in N,N-dimethylformamide (6mL). After 5 min solution of 3-amino-7-bromochroman-4-one hydrochloride(2.5 g, 8.9 mmol) and N-methylmorpholine (2.14 mL, 19.4 mmol) inN,N-dimethylformamide (6 mL) was added. After 1 hour the mixture wasdiluted with ethyl acetate (100 mL) and was with water (2×25 mL),saturated sodium bicarbonate (25 mL), saturated ammonium chloride (25mL) and dried over sodium sulfate. The mixture was filtered and thesolvent was removed under reduced pressure. The residue was subjected toflash chromatography with eluant of (10% methanol in ethylacetate) andhexane. The product containing fractions were combined and the solventwas removed under reduced pressure to provide (2S)-tert-butyl2-(7-bromo-4-oxochroman-3-ylcarbamoyl)pyrrolidine-1-carboxylate (3.23 g,7.35 mmol, 84%).

(S)-tert-butyl2-(7-bromo-3,4-dihydrochromeno[4,3-d]imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (2S)-tert-butyl2-(7-bromo-4-oxochroman-3-ylcarbamoyl)pyrrolidine-1-carboxylate (3.23 g,7.35 mmol) and ammonium acetate (5.6 g, 73.5 mmol) in xylenes (40 mL)was heated at 130° C. for 2 hours. The reaction was cooled to roomtemperature. The xylenes were removed under reduced pressure and theresidue was diluted with dichloromethane (100 mL). Saturated sodiumbicarbonate (200 mL) was added slowly with stirring until gas evolutionhad subsided. The phases were separated and the aqueous phase wasextracted with dichloromethane (50 mL). The combined organic phases werewashed with brine (50 mL) and dried over sodium sulfate. The mixture wasfiltered and the solvent was removed under reduced pressure. The residuewas subjected to flash chromatography with eluant of (10% methanol inethylacetate) and hexane. The product containing fractions were combinedand the solvent was removed under reduced pressure to provide(S)-tert-butyl2-(7-bromo-3,4-dihydrochromeno[4,3-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.77 g, 4.21 mmol, 57%).

Example BU

(1-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(1-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester was prepared following Example DG substituting(S)-tert-butyl2-(7-bromo-3,4-dihydrochromeno[4,3-d]imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate.C₄₈H₅₀N₈O₇ calculated 850.4 observed [M+1]⁺ 851.2; rt=1.80 min.

Example BV

(1-{2-[7-(6-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(1-{2-[7-(6-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester was prepared was prepared following Example DGsubstituting (S)-tert-butyl2-(7-bromo-3,4-dihydrochromeno[4,3-d]imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylateand Dimethylamino-phenyl-acetic acid forMethoxycarbonylamino-phenyl-acetic acid. C₄₈H₅₂N₈O₅ calculated 820.4observed [M+1]⁺ 821.3; rt=1.57 min.

Example BW

[2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

[2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester was prepared following Example DG substituting(S)-tert-butyl2-(7-bromo-3,4-dihydrochromeno[4,3-d]imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylateand Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid for2-Methoxycarbonylamino-3-methyl-butyric acid. C₅₀H₅₂N₈O₈ calculated892.4 observed [M+1]⁺ 893.3; rt=1.79 min.

Example BX

[2-{2-[7-(6-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

[2-{2-[7-(6-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester was prepared following Example DG substituting(S)-tert-butyl2-(7-bromo-3,4-dihydrochromeno[4,3-d]imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylateand Dimethylamino-phenyl-acetic acid forMethoxycarbonylamino-phenyl-acetic acid andMethoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid for2-Methoxycarbonylamino-3-methyl-butyric acid. C₅₀H₅₄N₈O₆ calculated862.4 observed [M+1]⁺ 863.2; rt=1.58 min.

Example BY

6-Bromo-2-iodobenzo[b]thiophene

A solution of lithium diisopropylamide (2.0 M, 1.41 mL, 2.8 mmol) wasadded dropwise to a solution of 6-bromobenzo[b]thiophene (500 mg, 2.4mmol) in tetrahydrofuran (10 mL) at −78° C. under argon. After 30minutes a solution of iodine (716 mg, 2.8 mmol) in tetrahydrofuran (3mL) was added dropwise. The iodine quickly decolorized. After 30 minutesthe reaction was quenched with an aqueous solution of sodium sulfite(1.0 M, 10 mL). Brine (50 mL) was added and the mixture was extractedwith dichloromethane (3×25 mL), dried over sodium sulfate and filtered.The solvent was removed under reduced pressure to provide6-bromobenzo[b]thiophene (702 mg, 2.07 mmol, 88%).

(S)-tert-butyl2-(5-(4-(6-bromobenzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of 6-bromobenzo[b]thiophene (702 mg, 2.07 mmol),(S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(700 mg, 1.59 mmol), tetrakis(triphenylphosphine) palladium (0) (184 mg,0.15 mmol), potassium carbonate (440 mg, 3.19 mmol) in water (2 mL) anddimethoxyethane (10 mL) was heated in a microwave reactor at 130° C. for30 minutes. The dimethoxyethane was removed under reduced pressure. Theresulting residue was partitioned between water (15 mL) anddichloromethane (15 mL). The phases were separated and the aqueous phasewas extracted with dichloromethane (20 mL). The combined organicextracts were dried over sodium sulfate and filtered. The solvent wasremoved under reduced pressure and the resulting residue was subjectedto flash chromatography with eluant of (10% methanol in ethyl acetate)and hexane. The product containing fractions were combined and thesolvent was removed under reduced pressure to provide (S)-tert-butyl2-(5-(4-(6-bromobenzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(302 mg, 0.58 mmol, 36%).

(S)-tert-butyl2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-tert-butyl2-(5-(4-(6-bromobenzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(302 mg, 0.57 mmol), bis(pinacolato)diboron (292 mg, 1.15 mmol),potassium acetate (113 mg, 1.15 mmol) and tetrakis(triphenylphosphine)palladium (0) (66 mg, 0.0575 mmol) in dimethoxyethane (5 mL) was heatedat 80° C. for 16 h hours. The solvent was removed under reducedpressure. The resulting residue was taken up in dichloromethane (10 mL)and washed with half saturated sodium bicarbonate (5 mL), brine (5 mL)and dried over sodium sulfate. The mixture was filtered and the solventwas removed under reduced pressure. The resulting residue was subjectedto flash chromatography with eluant of (10% methanol in ethyl acetate)and hexane. The product containing fractions were combined and thesolvent was removed under reduced pressure to provide (S)-tert-butyl2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(328 mg, 0.56 mmol, 98%).

Methyl(R)-2-oxo-1-phenyl-2-((S)-2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethylcarbamate

A solution of hydrogen chloride in dioxane (4 N, 5 mL) was added to asolution of (S)-tert-butyl2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(328 mg, 0.56 mmol) in dichloromethane (5 mL). Gas evolution wasobserved. After 20 min the solvent was removed under reduced pressureand the residue was placed under high vacuum for 30 min. The solid wastaken up in N,N-dimethylformamide (3 mL) and N-methylmorpholine (158 μL,1.43 mmol) was added to the solution. In a separate vessel, COMU (258mg, 0.605 mmol), and N-methylmorpholine (158 jL, 1.43 mmol) were addedto a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (126mg, 0.604 mmol) in dichloromethane (3 mL). This was stirred for 5minutes and both solutions were combined. After 15 minutes the mixturewas diluted with ethyl acetate (20 mL) and washed with water (5 mL) andbrine (5 mL). The organic phase was dried over sodium sulfate andfiltered. The solvent was removed under reduced pressure and the residuewas subjected to flash chromatography with eluant of (10% methanol inethyl acetate) and hexane. The product containing fractions werecombined and the solvent was removed under reduced pressure to providemethyl(R)-2-oxo-1-phenyl-2-((S)-2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethylcarbamate(261 mg, 0.39 mmol, 69%).

(S)-tert-Butyl2-(4-(2-(4-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of methyl(R)-2-oxo-1-phenyl-2-((S)-2-(5-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethylcarbamate(261 mg, 0.39 mmol), (S)-tert-butyl2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (125 mg, 0.39mmol), and tetrakis(triphenylphosphine) palladium (0) (45 mg, 0.039mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (29 mg, 0.039 mmol), potassium carbonate (109mg, 0.78 mmol), dimethoxyethane (5 mL), and water (1 mL) was heated at85° C. for 16 hours. The solvent was removed under reduced pressure andthe residue was take up in dichloromethane (15 mL) and washed with water(5 mL) and brine (5 mL). The organic phase was dried over sodium sulfateand filtered. The solvent was removed under reduced pressure and theresidue was subjected to flash chromatography with eluant of (10%methanol in ethyl acetate) and hexane. The product containing fractionswere combined and the solvent was removed under reduced pressure toprovide (S)-tert-Butyl2-(4-(2-(4-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(88 mg, 0.011 mmol, 28%).

Example BZ

[1-(2-{4-[2-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-benzo[b]thiophen-6-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{4-[2-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-benzo[b]thiophen-6-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example AA substituting(S)-tert-Butyl2-(4-(2-(4-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-11H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand 2-Methoxycarbonylamino-3-methyl-butyric acid forMethoxycarbonylamino-phenyl-acetic acid. C₄₅H₄₈N₈O₆S calculated 828.3observed [M+1]⁺ 829.5; rt=1.90 min.

Example CA

[1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-benzo[b]thiophen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-benzo[b]thiophen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example AA substituting2-{4-[2-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-benzo[b]thiophen-6-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester for (S)-tert-butyl2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.C₄₅H₄₈N₈O₆S calculated 828.3 observed [M+1]⁺ 829.5; rt=1.89 min.

Example CB

(S)-tert-butyl2-(5-(2-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-butyl2-(5-(2-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylatewas prepared following Example BY substituting (S)-tert-butyl2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.

Example CC

(2-Methoxy-1-{2-[5-(2-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-1H-naphtho[1,2-d]imidazol-7-yl}-benzo[b]thiophen-6-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

(2-Methoxy-1-{2-[5-(2-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-1H-naphtho[1,2-d]imidazol-7-yl}-benzo[b]thiophen-6-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester was prepared following Example BZsubstituting(S)-tert-butyl2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand 3-Methoxy-2-methoxycarbonylamino-butyric acid for2-Methoxycarbonylamino-3-methyl-butyric acid. C₄₇H₄₈N₈O₇S calculated868.3 observed [M+1]⁺ 868.8; rt=2.06 min.

Example CD

[2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-pyridin-3-yl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

[2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-pyridin-3-yl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester was prepared following Example DR substitutingMethoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid for2-Methoxycarbonylamino-3-methyl-butyric acid and2-(methoxycarbonylamino)-2-(pyridin-3-yl)acetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid. C₅₀H₅₁N₉O₇ calculated889.4 observed [M+1]⁺ 890.1; rt=1.76 min.

Example CE

(1-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-pyridin-3-yl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(1-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-pyridin-3-yl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester was prepared following Example DR substituting2-(methoxycarbonylamino)-2-(pyridin-3-yl)acetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid. C₄₈H₄₉N₉O₆ calculated847.4 observed [M+1]⁺ 847.9; rt=1.81 min.

Example CF

[1-(2-{4-[6-(4-{2-[1-(2-Ethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{4-[6-(4-{2-[1-(2-Ethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example ET substituting(R)-2-(ethylamino)-2-phenylacetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. C₄₇H₅₂N₈O₄ calculated792.4 observed [M+1]⁺ 793.4; rt=1.68 min.

Example CG

Methyl(S)-1-((S)-2-(4-(6-(4-(2-((S)-1-((R)-2-(cyclopropyl(ethyl)amino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

methyl(S)-1-((S)-2-(4-(6-(4-(2-((S)-1-((R)-2-(cyclopropyl(ethyl)amino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas prepared following Example ET substituting(R)-2-(cyclopropyl(ethyl)amino)-2-phenylacetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. C₅₀H₅₆N₈O₄ calculated832.4 observed [M+1]⁺ 833.3; rt=2.23 min.

Example CH

[1-(2-{4-[6-(4-{2-[1-(2-Dicyclopropylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{4-[6-(4-{2-[1-(2-Dicyclopropylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following Example ET substituting(R)-2-(dicyclopropylamino)-2-phenylacetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. C₅₁H₅₆N₈O₄ calculated844.4 observed [M+1]⁺ 845.2; rt=1.73 min.

Example CI

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-pyrazin-2-yl-acetyl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Prepared as{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-pyridin-3-yl-ethyl}-carbamicacid methyl ester (Example CL) from2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester.

LCMS-ESI⁺: calc'd for C₄₆H₄₈N₁₀O₆: 836.9 (M⁺). found: 837.8 (M+H⁺).

Example CJ

{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-pyrazin-2-yl-ethyl}-carbamicacid methyl ester

Prepared as{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-pyridin-3-yl-ethyl}-carbamicacid methyl ester (Example CL) replacing the amino acid derivative inthe final coupling step.

LCMS-ESI⁺: calc'd for C₄₈H₅₀N₁₀O₇: 878.9 (M⁺). found: 879.3 (M+H⁺).

Example CK

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-pyridin-3-yl-acetyl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Prepared as{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-pyridin-3-yl-ethyl}-carbamicacid methyl ester (Example CL) from2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester. LCMS-ESI⁺: calc'd for C₄₇H₄₉N₉O₆: 835.9 (M⁺).found: 836.4 (M+H⁺).

Example CL

[2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamicacid methyl ester

2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (350 mg, 0.717 mmol) was dissolved in DCM (8 mL)at room temperature. HCl (4N in dioxane, 8 mL) was added and stirring atroom temperature was continued. After all starting material wasconsumed, the volatiles were removed in vacuo and the crude material wasdissolved in DMF. Methoxy carbonylamino-(tetrahydro-pyran-4-yl)-aceticacid (155 mg, 0.715 mmol), DIEA (276.6 mg, 2.1 mmol), and HATU (272 mg,0.715 mmol) were added. After all starting material was consumed, thereaction was diluted with EtOAc and was washed with brine/aqueousbicarbonate. The organic layer was dried over sodium sulfate. Filtrationand evaporation of solvents in vacuo gave the crude product, which waspurified via flash chromatography on silica gel (eluent: EtOAc/hexanes)to yield 355 mg.

[2-[2-(5-{6-[4-(2-tert-Butoxycarbonylamino-acetyl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

[2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamicacid methyl ester (200 mg, 0.34 mmol),[2-(4-Bromo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (106 mg,0.34 mmol), Pd[PPh₃]₄ (39.2 mg, 0.034 mmol), potassium carbonate (117mg, 0.85 mmol) was heated at 120 C in the microwave for 22 minutes inDME (2.5 mL) and water (0.3 mL). Brine (1 mL) was added and the organiclayer was isolated and the volatiles were removed. The product waspurified via flash chromatography on silica gel (eluent: EtOAc/hexanes)to yield 183 mg.

2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester

[2-[2-(5-{6-[4-(2-tert-Butoxycarbonylamino-acetyl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester (183 mg, 0.265 mmol) was dissolved in DCM (2 mL) andHCl (4N in dioxane) was added. Stirring at room temperature wascontinued. After all starting material was consumed, all volatiles wereremoved in vacuo. The crude material was dissolved in DMF (1.5 mL) and4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (60.1mg, 0.265 mmol), DIEA (102 mg, 0.895 mmol), and HATU (100.7 mg, 0.265mmol) were added and stirring at room temperature was continued. Thecrude reaction was diluted with EtOAc and washed with brine/aqueousbicarbonate solution. The organic layer was dried over sodium sulfate.Filtration and evaporation of solvents gave the crude product (240 mg).The material was dissolved in m-xylenes (4 mL) at 130° C. Ammoniumacetate (200 mg) was added and the reaction was heated at 130° C. After2 hours the reaction was cooled to room temperature. All volatiles wereremoved in vacuo and the crude material was partitioned between EtOAcand brine/aqueous sodium bicarbonate solution. The organic layer wasdried over sodium sulfate. Filtration and evaporation of solvents gavethe crude product. Purification via flash chromatography yielded theproduct (170.4 mg).

{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-pyridin-3-yl-ethyl}-carbamicacid methyl ester

2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester (64 mg, 0.0816 mmol) was dissolved in DCM (1 mL)and HCl (4N dioxane, 1 mL) was added. After 20 minutes all volatileswere removed in vacuo. The crude material was dissolved in DMF (1 mL)and Methoxycarbonylamino-pyridin-3-yl-acetic acid/NaCl (1:1, 22 mg,0.0816 mmol), HATU (31 mg, 0.0816 mmol), and DIEA (31.5 mg, 0.245 mmol)were added and stirring at room temperature was continued. After 30minutes, aqueous HCl (1N, 0.1 mL) was added and the reaction mixture waspurified via RP-HPLC (eluent: water/MeCN w/0.1% TFA). The productcontaining fractions were lyophilized to yield the product (8.9 mg).

LCMS-ESI⁺: calc'd for C₄₉H₅₁N₉O₇: 877.9 (M⁺). found: 878.1 (M+H⁺).

Example CM

[2-(8-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

Synthesized similar to(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester with the corresponding amino acid carbamatereplacements.

LCMS-ESI⁺: calc'd for C₅₁H₅₄N₈O₉: 923.0 (M⁺). found: 923.8 (M+H⁺).

Example CN

[2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

Prepared as{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-pyridin-3-yl-ethyl}-carbamicacid methyl ester from2-{5-[4-(6-{2-[1-benzyloxycarbonyl-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester; using an HCl mediated deprotection and amide bondformation prior to an HBr mediated deprotection and second amide bondformation.

LCMS-ESI⁺: calc'd for C₅₀H₅₂N₈O₇: 876.9 (M⁺). found: 877.5 (M+H⁺).

Example CO

[2-(4-Bromo-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methyl-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

Isolated from the reaction mixture leading to[2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester LCMS-ESI⁺: calc'd for C₅₀H₅₃BrN₈O₇: 957.9 (M⁺). found:956.9/959.7 (M+H⁺).

Example CP

{2-[8-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-1,4-dioxa-7-aza-spiro[4.4]non-7-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester

Synthesized similar to(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester with the corresponding amino acid carbamatereplacements.

LCMS-ESI⁺: calc'd for C₅₁H₅₄N₈O₉: 923.0 (M⁺). found: 923.3 (M+H⁺).

Example CQ

{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester

Prepared as{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-2-oxo-1-pyridin-3-yl-ethyl}-carbamicacid methyl ester replacing the amino acid derivative in the finalcoupling step.

LCMS-ESI⁺: calc'd for C₅₀H₅₂N₈O₇: 876.9 (M⁺). found: 877.2 (M+H⁺).

Example CR

(1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-1,4-dihydro-chromeno[3,4-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Synthesized similar to(1-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester with the correspondingmethoxycarbonylamino-phenyl-acetic acid replacement.

LCMS-ESI⁺: calc'd for C₄₈H₅₀N₈O₇: 850.9 (M⁺). found: 851.3 (M+H⁺).

Example CS

[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Synthesized similar to[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester replacing the methoxycarbonylamino-phenyl-acetic acidwith dimethylamino-phenyl-acetic acid.

LCMS-ESI⁺: calc'd for C₄₈H₅₁N₉O₄: 817.9 (M⁺). found: 818.4 (M+H⁺).

Example CT

[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Synthesized similar to[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using[1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester and2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylicacid tert-butyl ester and methoxycarbonylamino-phenyl-acetic acid.

LCMS-ESI⁺: calc'd for C₄₈H₄₉N₉O₆: 847.9 (M⁺). found: 848.6 (M+H⁺).

Example CU

[1-(4-Cyano-2-{5-[6-(4-{2-[1-(2-dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Synthesized similar to[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using[1-(4-Cyano-2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester and2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acidtert-butyl ester and dimethylamino-phenyl-acetic acid.

LCMS-ESI⁺: calc'd for C₄₈H₅₁N₉O₄: 817.9 (M⁺). found: 818.5 (M+H⁺).

Example CV

[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Synthesized similar to[1-(2-{4-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-oxo-pyrrolidin-2-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester with the corresponding amino acid carbamatereplacements.

LCMS-ESI⁺: calc'd for C₄₈H₄₇N₉O₇: 861.9 (M) found: 862.3 (M+H⁺).

Example CW

[1-(4-Cyano-2-{5-[6-(4-{2-[1-(2-dimethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Synthesized similar to[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using[1-(4-Cyano-2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester and2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acidtert-butyl ester and dimethylamino-phenyl-acetic acid.

LCMS-ESI⁺: calc'd for C₄₈H₅₁N₉O₄: 817.9 (M⁺). found: 818.5 (M+H⁺).

Example CX

4-Cyano-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (202 mg, 0.392 mmol),4-Cyano-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (181 mg, 0.392 mmol), Pd[PPh₃](45.6 mg, 0.0392mmol), potassium carbonate (108 mg, 0.784 mmol) were heated in DME (3mL)/water (0.4 mL) at 120° C. for 20 minutes under microwave conditions.The volatiles were removed in vacuo and the crude was partitionedbetween EtOAc and brine/aqueous sodium bicarbonate solution. The organiclayer was dried over sodium sulfate. Filtration and evaporation ofsolvents yielded the crude material, which was purified via flashchromatography on silica gel to yield the product. (161 mg).

[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

4-Cyano-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (102.0 mg, 0.134 mmol) was stirred in DCM (2.0mL)/HCl in dioxane (4M, 2.0 mL). After 40 minutes all volatiles wereremoved in vacuo. The crude material was dissolved in DMF (1.5 mL) andmethoxycarbonylamino-phenyl-acetic acid (28.2 mg, 0.134 mmol), DIEA(52.2 mg, 0.4 mmol), and COMU (57.7 mg, 0.134 mmol) was added andstirring at room temperature was continued. After 15 minutes, thereaction was quenched with aqueous HCl (1N, 0.1 mL). The crude reactionmixture was purified via RP-HPLC (eluent: water/MeCN w/0.1% TFA). Theproduct containing fractions were lyophilized to give the final compound(59.3.0 mg).

LCMS-ESI⁺: calc'd for C₄₉H₄₉N₉O₆: 859.9 (M⁺). found: 860.4 (M+H⁺).

Example CY

[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Synthesized similar to[1-(2-{5-[6-(4-{2-[4-Cyano-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, reverting the order of Suzuki coupling and reactionintroduction of the amino acid moiety on the cyano proline usingmethoxycarbonylamino-phenyl-acetic acid.

LCMS-ESI⁺: calc'd for C₄₈H₄₉N₉O₆: 847.9 (M⁺). found: 848.5 (M+H⁺).

Example CZ

2-Chloro-1-[6-(2-chloro-acetyl)-1,5-dithia-s-indacen-2-yl]-ethanone

1,5-Dithia-s-indacene (100 mg, 0.526 mmol) was dissolved in THF (8 mL)and cooled to −78° C. n-BuLi solution (1.6M, 0.723 mL) was added andstirring at −78° C. was continued. After 120 the amide was added as asolution in THF (0.5 mL). After 30 min the reaction was quenched withammonium chloride aqueous solution and was warmed to room temperature.The aqueous layer was removed and MeOH (8 mL) was added. The resultantsolid was collected; crude yield 132.6 mg.

(1-(2-[5-(6-{2-[1-Boc-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-1,5-dithia-s-indacen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-Boc

The crude material from the previous step (132.6 mg, 0.388 mmol),4-methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.194mg, 0.855 mmol), potassium carbonate (160 mg) and sodium iodide (20 mg)were heated in acetone at 60° C. for 2 hours and cooled to roomtemperature. The crude reaction mixture was partitioned between EtOAcand brine/aqueous sodium bicarbonate solution. The organic layer wasdried over sodium sulfate. Filtration and evaporation of solvents givesthe crude his ester product (259.2 mg).

The bis-ester (259.2 mg) was dissolved in m-xylenes and heated at 135°C. Solid ammonium acetate (270 mg) was added and the reaction was heatedat 135° C. for 3 hours. The reaction was cooled to room temperature andthe volatiles were removed in vacuo. The crude product was partitionedbetween EtOAc and brine/aqueous sodium bicarbonate solution. The organiclayer was dried over sodium sulfate. Filtration and evaporation ofsolvents gives the crude product. Purification via chromatography onsilica gel yielded the product (84.5 mg).

(1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-1,5-dithia-s-indacen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The product of the previous step (28.0 mg, 0.041 mmol) was stirred inDCM (0.7 mL)/HCl in dioxane (4M, 0.6 mL). After 45 minutes all volatileswere removed in vacuo. The crude material was dissolved in DMF (1 mL)and valine carbamate (15.7 mg, 0.0899 mmol), DIEA (23.2 mg, 0.180 mmol),and COMU (38.4 mg, 0.0899 mmol) was added and stirring at roomtemperature was continued. After 15 minutes, the reaction was quenchedwith water (0.1 mL). The crude reaction mixture was purified via RP-HPLC(eluent: water/McCN w/0.1% TFA). The product containing fractions werelyophilized to give the final compound (18.0 mg).

LCMS-ESI⁺: calc'd for C₄₀H₄₆N₈O₆S₂: 798.9 (M⁺). found: 799.4 (M+H⁺).

Example DA

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-oxo-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

Synthesized similar to[1-(2-{4-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-oxo-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using4-Hydroxy-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester in the oxidation reaction.

LCMS-ESI⁺: calc'd for C₄₇H₄₈N₈O₇: 836.9 (M⁺). found: 837.4 (M+H⁺).

Example DB

methyl(S)-1-((S)-2-(5-(6-((2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)ethynyl)naphthalen-2yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(6-((2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:MS (ESI) m/z 771 [M+H]⁺.

Example DC

methyl(S)-1-((2S,4S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-4-cyanopyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-4-cyanopyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:MS (ESI) m/z 848 [M+H]⁺.

Example DD

methyl(S)-1-((S)-2-(5-(4-(6-(2-((2S,4S)-4-cyano-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazo-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(4-(6-(2-((2S,4S)-4-cyano-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazo-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:MS (ESI) m/z 818 [M+H]⁺.

Example DE

methyl(S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-4,4-difluoro-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-4,4-difluoro-1-oxobutan-2-ylcarbamate:MS (ESI) m/z 845 [M+H]⁺.

Example DF

methyl(S)-1-((2S,4R)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-4-cyanopyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4R)-2-(5-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-4-cyanopyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:MS (ESI) m/z 848 [M+H]⁺.

Example DG

(S)-tert-butyl2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-butyl2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.52 g, 3.63 mmol), bis(pinacolato)diboron (1.11 g, 4.36 mmol), KOAc(1.07 g, 10.89 mmol) and Pd(dppf)Cl₂ (266 mg, 0.363 mmol) were combinedin dioxane (18 mL). The reaction mixture was degassed for 10 min withbubbling N₂, then heated to 90° C. for 2 h 15 min before being cooled toRT. The mixture was then diluted with EtOAc and washed with saturatedaqueous NaHCO₃ and brine. The organic phase was dried over MgSO₄,filtered and concentrated. The crude residue was purified by silicacolumn chromatography (50% to 100% EtOAc/hexane) to afford the titlecompound (1.23 g, 73%).

(S)-tert-butyl2-(7-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-butyl2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(574 mg, 1.23 mmol), methyl(S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(616 mg, 1.23 mmol), Pd(PPh₃)₄ (142 mg, 0.123 mmol), and K₂CO₃ (2M inH₂O, 1.2 mL, 2.4 mmol) were combined in DME. The reaction mixture wasdegassed with bubbling N₂ for 10 min, then heated to 85° C. After 16 h,the reaction mixture was cooled to RT and concentrated. The cruderesidue was purified by silica column chromatography (0% to 30%MeOH/EtOAc) to afford the title compound (516 mg, 55%).

Methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-tert-butyl2-(7-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(246 mg, 0.325 mmol) was dissolved in dichloromethane (10 mL) and HCl (4M in dioxane, 2 mL) was added. After stirring at RT for 1 h 40 min, thereaction mixture was concentrated. The crude residue was treated with(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (75 mg, 0.358 mmol),COMU (139 mg, 0.325 mmol) and DMF (6 mL). DIPEA was added to the stirredreaction mixture dropwise. After 35 min, 1 mL H₂O was added and thecrude solution was purified by HPLC to afford the title compound (177mg, 64%). MS (ESI) m/z 849 [M+H]⁺.

Example DH

methyl(S)-1-((S)-2-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:MS (ESI) m/z 849 [M+H]⁺.

Example DI

methyl(S)-2-((S)-2-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Methyl(S)-2-((S)-2-(6-(4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate:MS (ESI) m/z 891 [M+H]⁺.

Example DJ

Methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(150 mg, 0.178 mmol) was dissolved in DCM (9 mL) and MnO₂ (155 mg, 1.78mmol) was added. After stirring for 16.5 h, more MnO₂ (619 mg, 7.12mmol) was added and the reaction mixture was heated to reflux. 1.5 hlater, 9 mL DCM were added and MnO₂ (619 mg, 7.12 mmol) was added. Afteranother 4 h, MnO₂ (619 mg, 7.12 mmol) was added. After and additional 16h, the reaction mixture was filtered over celite and concentrated. Thecrude residue was purified by HPLC to afford the title compound (42 mg,29%). MS (ESI) m/z 847 [M+H]⁺.

Example DK

methyl(S)-2-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Methyl(S)-2-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate:Title compound was synthesized using methods analogous to thepreparation of methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting methyl(S)-2-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamatefor methyl(S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.MS (ESI) m/z 891 [M+H]⁺.

Example DL

methyl(S)-2-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Title compound was synthesized using methods analogous to thepreparation of methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting methyl(S)-2-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamatefor methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.MS (ESI) m/z 889 [M+H]⁺.

Example DM

methyl(R)-2-((1R,3S,4S)-3-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamate

Methyl(R)-2-((1R,3S,4S)-3-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamate:MS (ESI) m/z 874 [M+H]⁺.

Example DN

methyl(S)-2-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamateMethyl(S)-2-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

MS (ESI) m/z 856 [M+H]⁺.

Example DO

methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateMethyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

MS: (ESI) m/z 856 [M+H]⁺.

Example DP

Methyl(S)-2-((S)-2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

(S)-tert-butyl2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(314 mg, 0.750 mmol) was dissolved in DCM (5 mL) and HCl (4M in dioxane,1 mL) was added. After stirring for 1 h, the reaction mixture wasconcentrated and the residue was treated with(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(163 mg, 0.750 mmol), HATU (285 mg, 0.750 mmol) and DMF (4 mL). Aftercooling to 0° C., DIPEA (0.65 mL, 3.75 mmol) was added dropwise and thereaction mixture was allowed to warm to RT. After 4 h, the mixture wasdiluted with EtOAc and washed with saturated aqueous NaHCO₃ and brine,dried over MgSO₄, filtered and concentrated. The crude residue waspurified by silica column chromatography (0% to 30% MeOH/EtOAc) toafford the title compound (211 mg, 54%).

(S)-tert-butyl2-(5-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Methyl(S)-2-((S)-2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate(211 mg, 0.408 mmol), (S)-tert-butyl2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(220 mg, 0.449 mmol), Pd(PPh₃)₄ (47 mg, 0.0408 mmol) and K₂CO₃ (2M inH₂O, 0.45 mL, 0.9 mmol) were suspended in DME (4 mL). The reactionmixture was degassed for 10 min with N₂ then heated to 85° C. After 17h, it was cooled to RT, diluted with MeOH, filtered over a thiol SPEcolumn and concentrated. The crude residue was purified by silica columnchromatography (0% to 40% MeOH/EtOAc) to afford the title compound (130mg, 40%).

Methyl(S)-2-((S)-2-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

(S)-tert-butyl2-(5-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(136 mg, 0.17 mmol) was dissolved in DCM (5 mL) and HCl (4M in dioxane,1 mL) was added. After stirring for 1 h, the reaction mixture wasconcentrated and the residue was treated with(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (36 mg, 0.170 mmol),COMU (73 mg, 0.170 mmol) and DMF (3 mL). DIPEA (0.12 mL, 0.68 mmol) wasadded dropwise. After 20 min, the reaction was quenched by addition ofH₂O and the crude mixture was purified by HPLC to afford the titlecompound (57 mg, 38%). MS: (ESI) m/z 891 [M+H]⁺.

Example DQ

Methyl(S)-2-((S)-2-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Methyl(S)-2-((S)-2-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate(51 mg, 0.0572 mmol) was dissolved in DCM (10 mL) and MnO₂ (995 mg,11.45 mmol) was added. After stirring at reflux for 4d, the reactionmixture was diluted with MeOH, filtered over celite and concentrated.The crude residue was dissolved in MeOH, filtered over a bicarbonate SPEand concentrated to afford the title compound (35 mg, 69%). MS: (ESI)m/z 889 [M+H]⁺.

Example DR

Methyl(S)-1-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.10 g, 2.64 mmol) was dissolved in DCM (15 mL) and HCl (4M in dioxane,3 mL) was added. After stirring for 2.5 h, the reaction mixture wasconcentrated and the residue was treated with(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (462 mg, 2.64 mmol),HATU (1.003g, 2.64 mmol) and DMF (13 mL). The stirred mixture was cooledto 0° C. and DIPEA (2.3 mL, 13.2 mmol) was added. After 7 min, thereaction was allowed to warm to RT. 20 min later, the mixture wasdiluted with EtOAc and washed with saturated aqueous NaHCO₃ and brine.The organic phase was dried over MgSO₄, filtered and concentrated. Thecrude residue was purified by silica column chromatography (79% to 100%EtOAc/hexane) to afford the title compound (590 mg, 47%).

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

Methyl(S)-1-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(590 mg, 1.25 mmol), bis(pinacolato)diboron (353 mg, 1.50 mmol), KOAc(245 mg, 2.50 mmol) and Pd(dppf)Cl₂ (91 mg, 0.125 mmol) were suspendedin dioxane (12 mL). The stirred mixture was degassed with N₂ for 11 minthen heated to 90° C. After 2.5 h, the mixture was cooled to RT, dilutedwith EtOAc and washed with saturated aqueous NaHCO₃ and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated. The cruderesidue was purified by silica column chromatography (80% to 100%EtOAc/hexane) to afford the title compound (425 mg, 65%).

(S)-tert-butyl2-(5-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(267 mg, 0.513 mmol), (S)-tert-butyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(272 mg, 0.616 mmol), Pd(PPh₃)₄ (59 mg, 0.0513 mmol) and K₂CO₃ (2M inH₂O, 0.62 mL, 1.2 mmol) were suspended in DME (5 mL). The mixture wasdegassed with N₂ for 10 min then heated to reflux. After 5 h, thereaction mixture was cooled to RT, diluted with EtOAc and washed withbrine. The organic phase was dried over MgSO₄, filtered andconcentrated. The crude residue was purified by silica columnchromatography (0% to 30% MeOH/EtOAc) to afford the title compound (201mg, 52%).

Methyl(S)-1-((S)-2-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-tert-butyl2-(5-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(88 mg, 0.116 mmol) was dissolved in DCM (5 mL) and HCl (4M in dioxane,1 mL) was added. After stirring for 1 h, the reaction mixture wasconcentrated and the residue was treated with(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (24 mg, 0.116 mmol),COMU (50 mg, 0.116 mmol) and DMF (3 mL). DIPEA (0.101 mL, 0.58 mmol) wasadded and the mixture was stirred for 13 min before being quenched withH₂O and purified by HPLC to afford the title compound (61 mg, 62%). MS:(ESI) m/z 847 [M+H]⁺.

Example DS

methyl(S)-2-((S)-2-(7-((4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Methyl(S)-2-((S)-2-(7-((4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate:MS: (ESI) m/z 863 [M+H]⁺.

Example DT

methyl(S)-2-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Methyl(S)-2-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate:MS: (ESI) m/z 857 [M+H]⁺.

Example DU

methyl(S)-1-((S)-2-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:MS: (ESI) m/z 850 [M+H]⁺.

Example DV

methyl(S)-1-((R)-3-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)morpholino)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((R)-3-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)morpholino)-3-methyl-1-oxobutan-2-ylcarbamate:MS: (ESI) m/z 866 [M+H]⁺.

Example DW

methyl(S)-1-((R)-3-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)morpholino)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((R)-3-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)morpholino)-3-methyl-1-oxobutan-2-ylcarbamate:(ESI) m/z 864 [M+H]⁺.

Example DX

methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:(ESI) m/z 858 [M+H]⁺.

Example DY

methyl(S)-1-((S)-2-(5-(4-((2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(4-((2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:(ESI) m/z 829 [M+H]+⁺.

Example DZ

methyl(R)-2-((S)-2-(5-(4-((2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamateMethyl(R)-2-((S)-2-(5-(4-((2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

(ESI) m/z 821 [M+H]⁺.

Example EA

(1R,3S,4S)-tert-butyl3-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(396 mg, 0.761 mmol), (1R,3S,4S)-tert-butyl3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(382 mg, 0.913 mmol), Pd(PPh₃)₄ (88 mg, 0.0761 mmol) and K₂CO₃ (2M inH₂O, 0.95 mL, 1.9 mmol) were suspended in DME (4 mL). The reactionmixture was degassed with N₂ for 6 min then heated to reflux. After 6.5h, the reaction mixture was cooled to RT, diluted with MeOH, filteredover a thiol SPE column and concentrated. The crude residue was purifiedby column chromatography (0% to 30% MeOH/EtOAc) to afford the titlecompound (461 mg, 83%).

Methyl(S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(1R,3S,4S)-tert-butyl3-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(73 mg, 0.0997 mmol) was dissolved in DCM (5 mL) and treated with HCl(4M in dioxane, 1 mL). After 3 h, the reaction mixture was concentrated.The residue was treated with(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (23 mg, 0.120mmol), COMU (51 mg, 0.120 mmol) and DMF (2 mL). DIPEA (0.090 mL, 0.499mmol) was added and the reaction mixture was stirred for 25 min beforebeing quenched with H₂O and purified by HPLC to afford the titlecompound (22 mg, 28%). (ESI) m/z 805 [M+H]⁺.

Example EB

methyl(S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:Title compound was prepared by methods analogous to those described formethyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid for(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 789[M+H]⁺.

Example EC

methyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((R)-2-methoxycarbonylamino-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((R)-2-methoxycarbonylamino-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:Title compound was prepared by methods analogous to those described formethyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (R)-2-(methoxycarbonyl amino)-2-phenylacetic acid for(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 823[M+H]⁺.

Example ED

methyl(R)-2-((S)-2-(5-(4-((2-((S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

Methyl(R)-2-((S)-2-(5-(4-((2-((S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate:(ESI) m/z 837 [M+H]⁺.

Example EE

methyl(R)-2-((S)-2-(5-(6-(2-((S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

Methyl(R)-2-((S)-2-(5-(6-(2-((S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate:Title compound was prepared according to the methods described formethyl(S)-1-((S)-2-(7-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. (ESI) m/z 863[M+H]⁺.

Example EF

methyl(S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateMethyl(S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Title compound was prepared by methods analogous to those described formethyl(S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 831[M+H]⁺.

Example EG

(1R,3S,4S)-tert-butyl3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(372 mg, 0.715 mmol), (1R,3S,4S)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(317 mg, 0.715 mmol), Pd(PPh₃)₄ (83 mg, 0.0715 mmol) and K₂CO₃ (2M inH₂O, 0.7 mL, 1.4 mmol) were suspended in DME (3.6 mL). The mixture wasdegassed for 13 min with bubbling N₂, then heated to reflux. After 18 h,the reaction mixture was cooled to RT and 5 mL MeOH was added. EtOAc wasadded and the organics were washed with saturated aqueous NaHCO₃ andbrine, dried over MgSO₄, filtered and concentrated. The crude residuewas purified by silica column chromatography (0% to 33% MeOH/EtOAc) toafford the title compound (196 mg, 36%).

Methyl(S)-1-((S)-2-(2′-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(1R,3S,4S)-tert-butyl3-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(102 mg, 0.135 mmol) was dissolved in DCM (5 mL) and treated with HCl(4M in dioxane, 1 mL). After 2 h, the reaction mixture was concentrated.The residue was treated with(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (28 mg, 0.149 mmol),COMU (58 mg, 0.135 mmol) and DMF (3 mL). DIPEA (0.12 mL, 0.675 mmol) wasadded and the reaction mixture was stirred for 1.5 h before beingquenched with H₂O and purified by HPLC to afford the title compound (86mg, 77%). (ESI) m/z 814 [M+H]⁺.

Example EH

methyl(S)-1-((S)-2-(2′-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(2′-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:Title compound was prepared by methods analogous to those described formethyl(S)-1-((S)-2-(2′-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. (ESI) m/z 830[M+H]⁺.

Example EI

methyl(S)-1-((S)-2-(2′-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(2′-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:Title compound was prepared by methods analogous to those described formethyl(S)-1-((S)-2-(2′-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. (ESI) m/z 855[M+H]⁺.

Example EJ

methyl(S)-2-((1R,3S,4S)-3-(7-((4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Methyl(S)-2-((1R,3S,4S)-3-(7-((4-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate:(ESI) m/z 890 [M+H]⁺.

Example EK

methyl(S)-1-((S)-2-(2′-((S)-7-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-4′,5′-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(2′-((S)-7-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-4′,5′-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:(ESI) m/z 863 [M+H]⁺.

Example EL

methyl(S)-1-((S)-2-(2′-((S)-7-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-4′,5′-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(2′-((S)-7-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-4′,5′-dihydro-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:(ESI) m/z 889 [M+H]⁺.

Example EM

methyl(S)-1-((S)-2-(5-(4-(2-((S)-7-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(4-(2-((S)-7-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:(ESI) m/z 838 [M+H]⁺.

Example EN

methyl(8)-1-((S)-2-(5-(4-(2-((S)-7-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateMethyl(S)-1-((S)-2-(5-(4-(2-((S)-7-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(ESI) m/z 864 [M+H]⁺.

Example EO

(1R,4S)-tert-butyl3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Title compound was prepared by methods analogous to those described for(1R,4S)-tert-butyl3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate,substituting 2-bromo-1-(4-bromo-3-fluorophenyl)ethanone for2-bromo-1-(4-bromophenyl)ethanone.

Methyl(2S,3R)-1-((1R,4S)-3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate

(1R,4S)-tert-butyl3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylatewas dissolved in DCM (5 mL) and treated with HCl (4M in dioxane, 1 mL).After 1 h, the reaction mixture was concentrated. The residue wastreated (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (76 mg,0.406 mmol), HATU (154 mg, 0.406 mmol) and DMF (4 mL). The stirredreaction mixture was cooled to 0° C., DIPEA (0.35 mL, 2.03 mmol) wasadded dropwise and the reaction mixture was warmed to RT. After 20 min,it was diluted with EtOAc and washed with saturated aqueous NaHCO₃ andbrine, dried over MgSO₄, filtered and concentrated. The crude residuewas purified by silica column chromatography (0% to 33% MeOH/EtOAc) toafford the title compound (162 mg, 78%).

Methyl(2S,3R)-1-((1R,4S)-3-(5-(4-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate

Methyl(2S,3R)-1-((1R,4S)-3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate(162 mg, 0.318 mmol), methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(199 mg, 0.382 mmol), Pd(PPh₃)₄ (37 mg, 0.0318 mmol) and K₂CO₃ (2M inH₂O, 0.4 mL, 0.8 mmol) were suspended in DME (3 mL). The reactionmixture was degassed with N₂ for 11 min then heated to reflux for 2.5 h.Upon completion, the reaction mixture was diluted with MeOH, filteredover a thiol SPE column and concentrated. The crude residue was purifiedby silica column chromatography (0% to 50% MeOH/EtOAc) to afford thetitle compound (125 mg, 48%). (ESI) m/z 823 [M+H]⁺.

Example EP

2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acidtert-butyl ester (1.00 g, 2.5 mmol) and[2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,332]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (1.97 g, 3.6 mmol, 1.5 equiv.) in DME (12.5 mL) wasadded K₃PO₄ (aqueous, 2 M, 3.9 mL, 7.8 mmol, 3 equiv.), Pd₂dba₃ (0.12 g,0.13 mmol, 0.05 equiv.), and Xantphos (0.15 g, 0.26 mmol, 0.1 equiv.).The slurry was degassed with argon for 5 minutes and heated to 80° C.for 18 hours. The resulting reaction mixture was diluted with EtOAc/MeOH(10:1) and filtered through celite. The solution was washed with waterand brine. The aqueous layer was back-extracted with EtOAc and thecombined organic layers were dried over Na₂SO₄ and concentrated. Thecrude oil was purified by column chromatography (SiO₂, 50→100% EtOAc inHexanes) to provide2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.93 g, 49%) as a yellow powder. LCMS-ESI⁺:calc'd for C₄₂H₄₉N₇O₅: 731.4 (M⁺). Found: 732.9 (M+H⁺).

Example EQ

2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester was prepared following the procedure for2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester, substituting(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester for2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acidtert-butyl ester and2-{5-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester for[2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester. LCMS-ESI⁺: calc'd for C₄₂H₄₉N₇O₅: 731.4 (M⁺). Found:732.9 (M+H⁺).

Example ER

2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester

2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-carboxylicacid benzyl ester was prepared following the procedure for Example Ausing pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester in place ofpyrrolidin-1,2-dicarboxylic acid 1-tert-Butyl ester. LCMS-ESI⁺: calc'dfor C₂₇H₃₂BN₃O₄: 473.37 (M⁺). Found: 474.47 (M+H⁺).

2-(5-{6-[4-(2-{1-[2-Benzyloxycarbonyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (2.26g, 5.11 mmol) and2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester (3.00 g, 6.34 mmol) in DME (25 mL) was addedTetrakis(triphenylphosphine)Palladium (0.30 g, 0.26 mmol) and aqueouspotassium phosphate (2M, 7.6 mL, 15.2 mmol). The solution was degassedwith argon for 15 min and heated to 80° C. for 18 h with stirring. Thesolution was cooled, filtered and diluted with EtOAc. The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated. The crude oilwas purified by column chromatography (SiO₂, 30→100% EtOAc (10% MeOH) inHexanes) to provide2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (4.31 g, 84%). LCMS-ESI⁺: calc'd for C₄₃H₄₄N₆O₄:708.34 (M⁺). Found: 709.58 (M+H⁺).

2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.25 g, 0.36 mmol) in EtOH (3.5 mL) was addedPalladium on carbon (10%, 0.42 g, 0.39 mmol) and Potassium Carbonate(0.10 g, 0.70 mmol). The slurry was stirred at room temperature under anatmosphere of H₂ for 72 h. The slurry was filtered through celite andwashed with EtOH. The filtrate was concentrated to an oil and dilutedwith CH₂Cl₂ (3 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-aceticacid (0.12 g, 0.46 mmol), HATU (0.17 g, 0.46 mmol), and DIPEA (0.13 mL,1.03 mmol) were added, and the solution was stirred at room temperaturefor 2 h. The solution was diluted with THF and LiOH (2.5 M, 0.25 mL) wasadded. The solution was concentrated to dryness and the crude oil waspurified by column chromatography (SiO₂, 30→100% EtOAc (10% MeOH) inHexanes to 60% MeOH in EtOAc) to provide2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.22 g, 79%). LCMS-ESI⁺: calc'd for C₄₄H₅₁N₇O₆:773.39 (M⁺). Found: 774.77 (M+H⁺).

[2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

To a solution of2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.22 g, 0.28 mmol) in CH₂Cl₂ (2.5 mL) and MeOH(0.1 mL) was added HCl (in dioxane, 4 M, 0.7 mL, 2.80 mmol). Thesolution was stirred at room temperature for 2 h and concentrated todryness. The resulting solid was slurried in CH₂Cl₂ (5 mL).Methoxycarbonylamino-phenyl-acetic acid (0.09 g, 0.42 mmol) andPotassium Phosphate (0.18 g, 0.84 mmol) were added and the resultingsolution was cooled to 0° C. (external, ice). COMU (0.15 g, 0.35 mmol)was added and the reaction was stirred at 0° C. for 2 h. Additional COMU(0.10 g) and DIPEA (0.15 mL, 0.86 mmol) was added and the reaction wasstirred for 2 h. The resulting red solution was concentrated and dilutedwith DMF and filtered. Purification by preparative HPLC (Gemini, 15→40%MeCN in H₂O (0.1% formic acid)) and lyophilization provided[2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester (0.05 g, 22%). LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₇:864.40 (M⁺). Found: 865.87 (M+H⁺).

Example ES

2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.25 g, 0.36 mmol) in EtOH (3.5 mL) was addedPalladium on carbon (10%, 0.42 g, 0.39 mmol) and Potassium Carbonate(0.10 g, 0.70 mmol). The slurry was stirred at room temperature under anatmosphere of H₂ for 72 h. The slurry was filtered through celite andwashed with EtOH. The filtrate was concentrated to an oil and dilutedwith CH₂Cl₂ (3 mL). Methoxycarbonylamino-phenyl-acetic acid (0.11 g,0.54 mmol) and Potassium Phosphate (0.08 g, 0.35 mmol) were added andthe resulting slurry was cooled to 0° C. (external, ice). COMU (0.19 g,0.44 mmol) was added and the reaction was stirred at 0° C. for 2 h. Theslurry was diluted with CH₂Cl₂ and filtered through celite. The filtratewas concentrated and purified by column chromatography (SiO₂, 30→100%EtOAc (10% MeOH) in Hexanes to 60% MeOH in EtOAc) to provide2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.20 g, 74%). LCMS-ESI⁺: calc'd for C₄₅H₄₇N₇O₅:765.36 (M⁺). Found: 766.64 (M+H⁺).

{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester

To a solution of2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.20 g, 0.26 mmol) in CH₂Cl₂ (2.5 mL) and MeOH(0.1 mL) was added HCl (in dioxanes, 4 M, 0.7 mL, 2.80 mmol). Thesolution was stirred at room temperature for 3 h and concentrated todryness. The resulting solid was slurried in CH₂Cl₂ (4 mL).Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.12 g, 0.54mmol), HATU (0.12 g, 0.33 mmol), and DIPEA (0.2 mL, 1.15 mmol) wereadded. The resulting solution was stirred at room temperature for 1 h.The solution was diluted with THF and LiOH (2.5 M, 0.1 mL) was added.The solution was concentrated to dryness and the crude oil was dilutedwith DMF and purified by preparative HPLC (Gemini, 15→40% MeCN in H₂O(0.1% formic acid)) and lyophilized to provide{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester (0.083 g, 37%). LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₇:864.40 (M⁺). Found: 866.01 (M+H⁺).

Example ET

2-Methoxycarbonylamino-2-phenyl-propionic acid

To a solution of 2-Amino-2-phenyl-propionic acid (1.00 g, 6.06 mmol) inTHF (17 mL), was added aqueous NaOH (6 M, 2.5 mL, 15.0 mmol) and MethylChloroformate (0.55 mL, 7.10 mmol). The solution was stirred for 18 h.Aqueous HCl (12 M, 1.5 mL, 18 mmol) was slowly added. The solution wasdiluted with HCl (1M) and extracted with Et₂O (3 times). The combinedorganic layers were extracted with NaOH (2N, 3 times). The aqueouslayers were acidified with HCl (12 N) and extracted with Et₂O (3 times).The combined organic layers were dried over MgSO₄ and concentrated. Thecrude oil was diluted in CH₂Cl₂ and concentrated again to provide2-Methoxycarbonylamino-2-phenyl-propionic acid (0.66 g, 49%). LCMS-ESI⁺:calc'd for C₁₁H₁₃NO₄: 223.08 (M⁺). Found: 223.97 (M+H⁺).

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.15 g, 0.205 mmol) in CH₂Cl₂ (2 mL) and MeOH(0.2 mL) was added HCl (in dioxanes, 4 M, 1.0 mL, 4.1 mmol). Thesolution was stirred at room temperature for 1 h and concentrated todryness. The resulting solid was dissolved in DMF (2.3 mL).2-Methoxycarbonylamino-2-phenyl-propionic acid (0.06 g, 0.29 mmol), COMU(0.12 g, 0.27 mmol) and DIPEA (0.2 mL, 1.15 mmol) were added. Thereaction was stirred at room temperature for 18 h before HCl (6M, 0.1mL) was added. The solution was purified by preparative HPLC (Gemini,15→40% MeCN in H₂O (0.1% formic acid)) and lyophilized to provide[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.072 g, 42%). LCMS-ESI⁺: calc'd for C₄₈H₅₂N₈O₆:836.40 (M⁺). Found: 837.87 (M+H⁺).

Example EU

Hydroxyimino-pyridin-2-yl-acetic acid ethyl ester

Hydroxyimino-pyridin-2-yl-acetic acid ethyl ester was prepared fromPyridin-2-yl-acetic acid ethyl ester following the procedure describedin J. Org. Chem. 1961, 26, 3373.

Methoxycarbonylamino-pyridin-2-yl-acetic acid ethyl ester

To a solution of Hydroxyimino-pyridin-2-yl-acetic acid ethyl ester (2.35g, 12.1 mmol) in EtOH (24 mL) was added Palladium on Carbon (10%, 0.64g, 0.61 mmol), Dimethyl dicarbonate (3.2 mL, 30.3 mmol) and cyclohexene(3.68 mL, 36.3 mmol). The reaction was heated to reflux for 4 h and thencooled to room temperature. The slurry was filtered and washed withEtOH. The filtrate was concentrated to dryness and purified by columnchromatography (SiO₂, 2→10% MeOH in CH₂Cl₂) to provideMethoxycarbonylamino-pyridin-2-yl-acetic acid ethyl ester (0.90 g, 31%).LCMS-ESI⁺: calc'd for C₁₁H₁₄N₂O₄: 238.10 (M⁺). Found: 239.06 (M+H⁺).

Methoxycarbonylamino-pyridin-2-yl-acetic acid

To a solution of Methoxycarbonylamino-pyridin-2-yl-acetic acid ethylester (0.26 g, 1.1 mmol) in THF (6.0 mL) and MeOH (2.0 mL) was addedaqueous LiOH (2.5 M, 2.2 mL, 5.5 mmol). The solution was stirred at roomtemperature for 1.5 h. The reaction was diluted with CH₂Cl₂ and washedwith aqueous ammonium chloride and brine. The aqueous layers werecombined and concentrated. The resulting solid was triterated with MeOHand filtered. The filtrated was concentrated and triterated a secondtime with MeOH. Concentration of the filtrate providedMethoxycarbonylamino-pyridin-2-yl-acetic acid which was used crude inthe next step. LCMS-ESI⁺: calc'd for C₉H₁₀N₂O₄: 210.06 (M⁺). Found:210.98 (M+H⁺).

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-pyridin-2-yl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.10 g, 0.0.14 mmol) in CH₂Cl₂ (1.3 mL) and MeOH(0.1 mL) was added HCl (in dioxanes, 4 M, 0.35 mL, 1.4 mmol). Thesolution was stirred at room temperature for 2 h and concentrated todryness. The resulting solid was dissolved in DMF (1.5 mL).Methoxycarbonylamino-pyridin-2-yl-acetic acid (assumed 0.23 g, 1.1mmol), HATU (0.06 g, 0.15 mmol) and DIPEA (0.12 mL, 0.69 mmol) wereadded. The solution was stirred at room temperature for 2 h. AdditionalHATU (0.13 g, 0.30 mmol) was added and the solution was stirred for 2 h.LiOH (2.5 M, 0.1 mL) was added and the reaction was concentrated. Thecrude oil was purified by preparative HPLC (Gemini, 15→40% MeCN in H₂O(0.1% formic acid)) and lyophilized to provide[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-pyridin-2-yl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.02 g, 22%). LCMS-ESI⁺: calc'd for C₄₆H₄₉N₉O₆:823.38 (M⁺). Found: 824.88 (M+H⁺).

Example EV

2-Methoxycarbonylamino-indan-2-carboxylic acid

To a solution of 2-Amino-indan-2-carboxylic acid (0.45 g, 1.63 mmol) inCH₂Cl₂ (16 mL) was added HCl (in dioxanes, 4 M, 0.41 mL, 1.63 mmol). Thesolution was stirred at room temperature for 2 h and concentrated todryness. The crude oil was dissolved in THF (6.5 mL). Aqueous NaOH (6 M,0.92 mL, 5.5 mmol) and Methyl Chloroformate (0.15 mL, 1.95 mmol) wereadded and the resulting slurry was stirred at room temperature for 18 h.The reaction was diluted with HCl (1N) and extracted with Et2O (3times). The combined organic layers were extracted with NaOH (2N, 3times). The aqueous layers were acidified with HCl (6 N) and extractedwith Et₂O (3 times). The combined organic layers were dried over MgSO₄and concentrated. The crude oil was diluted in hexanes and concentratedagain to provide 2-Methoxycarbonylamino-indan-2-carboxylic acid (0.35 g,92%). LCMS-ESI⁺: calc'd for C₁₂H₁₃NO₄: 235.08 (M⁺). Found: 235.94(M+H⁺).

[2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-2-yl]-carbamicacid methyl ester

To a solution of2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.15 g, 0.205 mmol) in CH₂Cl₂ (2 mL) and MeOH(0.2 mL) was added HCl (in dioxanes, 4 M, 1.0 mL, 4.1 mmol). Thesolution was stirred at room temperature for 1 h and concentrated todryness. The resulting solid was dissolved in DMF (2.5 mL).2-2-Methoxycarbonylamino-indan-2-carboxylic acid (0.07 g, 0.31 mmol),COMU (0.12 g, 0.27 mmol) and DIPEA (0.25 mL, 1.4 mmol) were added. Thereaction was stirred at room temperature for 18 h. The solution waspurified by preparative HPLC (Gemini, 15→40% MeCN in H₂O (0.1% formicacid)) and lyophilized to provide[2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-2-yl]-carbamicacid methyl ester (0.075 g, 31%). LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₆:848.40 (M⁺). Found: 849.97 (M+H⁺).

Example EW

[1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-1-yl]-carbamicacid methyl ester

[1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-1-yl]-carbamicacid methyl ester (0.13 g, 38%) was prepared following the procedure for[2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-2-yl]-carbamicacid methyl ester, substituting 1-Amino-indan-1-carboxylic acid for2-Amino-indan-2-carboxylic acid. LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₆:848.40 (M⁺). Found: 849.91 (M+H⁺).

Example EX

2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-acrylic acid methylester

To a solution of (Dimethoxy-phosphoryl)-methoxycarbonylamino-acetic acidmethyl ester (0.34 g, 1.35 mmol) in THF (5.4 mL) at −78° C. (external,Acetone/CO₂ bath) was added 1,1,3,3-tetramethguanidine (0.17 mL, 1.35mmol). The solution was stirred for 15 min beforeTetrahydro-pyran-4-carbaldehyde (0.15 g, 1.35 mmol) was added. Thereaction was stirred at −78° C. for 2 h and then allowed to warm to roomtemperature. The reaction was diluted with EtOAc and washed with HCl(1N) and brine. The aqueous layers were backextracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Thecrude oil was purified by column chromatography (SiO₂, 20→100% EtOAc inHexanes) to provide2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-acrylic acid methylester (0.15 g, 45%). LCMS-ESI⁺: calc'd for C₁₁H₁₇NO₅: 243.11 (M⁺).Found: 243.96 (M+H⁺).

2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid methylester

A solution of 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-acrylicacid methyl ester (0.14 g, 0.57 mmol) in MeOH (2.1 mL) and CH₂Cl₂ (0.21mL) was degassed with argon for 2 min. (S,S)-Me-BPE-Rh (0.02 g, 0.03mmol) was added and the solution was degassed with argon for anadditional 2 min. The solution was shaken on a Parr apparatus under anH₂ atmosphere (65 psi) for 3 days. The reaction was concentrated and thecrude oil was purified by column chromatography (SiO₂, 20→100% EtOAc inHexanes) to provide2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid methylester (0.11 g, 77%). LCMS-ESI⁺: calc'd for C₁₁H₁₉NO₅: 245.13 (M⁺).Found: 246.1 (M+H⁺).

2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid

To a solution of2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid methylester (0.11 g, 1.1 mmol) in THF (3.3 mL) and MeOH (1.1 mL) at 0° C.(external, ice bath) was added aqueous LiOH (1 M, 0.88 mL, 0.88 mmol).The solution was stirred at room temperature for 18 h and concentratedto provide 2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionicacid which was used crude in the next step. LCMS-ESI⁺: calc'd forC₁₀H₁₇NO₅: 231.11 (M⁺). Found: 231.99 (M+H⁺).

[2-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-ylmethyl)-ethyl]-carbamicacid methyl ester

To a solution of2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.12 g, 0.15 mmol) in CH₂Cl₂ (1.5 mL) and MeOH(0.2 mL) was added HCl (in dioxanes, 4 M, 0.75 mL, 3.0 mmol). Thesolution was stirred at room temperature for 2 h and concentrated todryness. The resulting solid was dissolved in DMF (1.5 mL).2-Methoxycarbonylamino-3-(tetrahydro-pyran-4-yl)-propionic acid (0.05 g,0.22 mmol), HATU (0.07 g, 0.19 mmol) and DIPEA (0.13 mL, 0.74 mmol) wereadded. The resulting solution was stirred at room temperature for 18 h.The solution was purified twice by preparative HPLC (Gemini, 15-40% MeCNin H₂O (0.1% TFA)) and lyophilized to provide[2-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-ylmethyl)-ethyl]-carbamicacid methyl ester (0.024 g, 18%). LCMS-ESI⁺: calc'd for C₅₀H₅₄N₈O₇:878.41 (M⁺). Found: 879.97 (M+H⁺).

Example EY

2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid benzyl ester

2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid benzyl ester (5.4 g, 74%) was prepared following the procedure for2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester, substituting Pyrrolidine-1,2-dicarboxylic acid1-benzyl ester for Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.LCMS-ESI⁺: calc'd for C₂₅H₂₂BrN₃O₂: 475.09 (M⁺). Found: 476.63 (M+H⁺).

4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester

4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester (2.28 g) was prepared following the procedure for2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester, substituting4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester forPyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI⁺: calc'dfor C₂₄H₃₂BF₂N₃O₄: 475.25 (M⁺). Found: 476.42 (M+H⁺).

2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid benzyl ester (1.5 g, 3.15 mmol) and4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester (1.8 g, 3.78 mmol) in DME (16 mL) was addedTetrakis(triphenylphosphine)Palladium (0.19 g, 0.16 mmol) and aqueouspotassium phosphate (2M, 4.8 mL, 9.6 mmol). The solution was degassedwith argon for 15 min and heated to 80° C. for 18 h with stirring. Thesolution was cooled, filtered and diluted with EtOAc (˜5% MeOH). Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The crude oil was purified by column chromatography (SiO₂, 30→100% EtOAc(10% MeOH) in Hexanes to 70% MeOH in EtOAc) to provide2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylicacid tert-butyl ester (2.1 g, 89%). LCMS-ESI⁺: calc'd for C₄₃H₄₂F₂N₆O₄:744.32 (M⁺). Found: 745.20 (M+H⁺).

2-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester

To a solution of2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylicacid tert-butyl ester (0.25 g, 0.34 mmol) in CH₂Cl² (3.5 mL) and MeOH(0.25 mL) was added HCl (in dioxanes, 4 M, 1.7 mL, 7.8 mmol). Thesolution was stirred at room temperature for 2.5 h and concentrated todryness. The resulting solid was slurried in CH₂Cl₂ (3 mL) and DMF (1mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.11 g,0.50 mmol), HATU (0.15 g, 0.40 mmol), and DIPEA (0.3 mL, 1.7 mmol) wereadded. The resulting solution was stirred at room temperature for 18 h.The solution was diluted with CH₂Cl₂ and washed with saturated sodiumbicarbonate. The organic layer was dried over Na₂SO₄ and concentrated.The crude oil was purified by column chromatography (SiO₂, 2→20% MeOH inCH₂Cl₂), followed by preparative HPLC (Gemini, 15→50% MeCN in H₂O (0.1%TFA)) to provide2-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester (0.13 g, 46%). LCMS-ESI⁺: calc'd for C₄₇H₄₇F₂N₇O₆:843.36 (M⁺). Found: 844.78 (M+H⁺).

[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

To a solution of2-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid benzyl ester (0.13 g, 0.15 mmol) in EtOH (3.5 mL) was addedPalladium on carbon (10%, 0.08 g, 0.08 mmol) and Potassium Carbonate(0.07 g, 0.48 mmol). The slurry was stirred at room temperature under anatmosphere of H₂ for 3 h. The slurry was filtered through celite andwashed with EtOH. The filtrate was concentrated to an oil and dilutedwith CH₂Cl₂ (3 mL) and filtered an additional time.Methoxycarbonylamino-phenyl-acetic acid (0.05 g, 0.03 mmol) andPotassium Phosphate (0.04 g, 0.16 mmol) were added and the resultingslurry was cooled to 0° C. (external, ice). COMU (0.09 g, 0.02 mmol) wasadded and the reaction was stirred at 0° C. for 2 h. The slurry wasdiluted with CH₂Cl₂ and filtered through celite. The filtrate wasconcentrated and purified by preparative HPLC (Gemini, 15→50% MeCN inH₂O (0.1% TFA)) to provide to provide[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester (0.03 g, 17%). LCMS-ESI⁺: calc'd for C₄₉H₅₀F₂N₈O₇:900.38 (M⁺). Found: 901.4 (M+H⁺).

Example EZ

4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylicacid tert-butyl ester (0.25 g, 0.34 mmol) in EtOH (3.5 mL) was addedPalladium on carbon (10%, 0.18 g, 0.02 mmol) and Potassium Carbonate(0.14 g, 1.0 mmol). The slurry was stirred at room temperature under anatmosphere of H2 for 5 h. The slurry was filtered through celite andwashed with EtOH. The filtrate was concentrated to an oil and dilutedwith CH₂Cl₂ (3 mL) and DMF (2 mL).Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.11 g, 0.50mmol), HATU (0.15 g, 0.40 mmol), and DIPEA (0.3 mL, 1.7 mmol) wereadded. The resulting solution was stirred at room temperature for 5 h.The solution was diluted with CH₂Cl₂ and washed with saturated sodiumbicarbonate. The organic layer was dried over Na₂SO₄ and concentrated.The crude oil was concentrated and purified by preparative HPLC (Gemini,15→50% MeCN in H₂O (0.1% TFA)) to provide to provide4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.04 g, 14%). LCMS-ESI⁺: calc'd for C₄₄H₄₉F₂N₇O₆:809.37 (M⁺). Found: 810.79 (M+H⁺).

{2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester

To a solution of4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.04 g, 0.05 mmol) in CH₂Cl₂ (0.5 mL) and MeOH(0.05 mL) was added HCl (in dioxanes, 4 M, 0.3 mL, 1.2 mmol). Thesolution was stirred at room temperature for 2 h and concentrated todryness. The solid was slurried with CH₂Cl₂ (0.5 mL).Methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.07 mmol) andPotassium Phosphate (0.03 g, 0.14 mmol) were added and the resultingslurry was cooled to 0° C. (external, ice). COMU (0.03 g, 0.06 mmol) wasadded and the reaction was stirred at room temperature for 2 h. Theslurry was diluted with CH₂Cl₂ and filtered through celite. The filtratewas concentrated and purified by preparative HPLC (Gemini, 15→50% MeCNin H₂O (0.1% TFA)) to provide to provide{2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester (0.02 g, 49%). LCMS-ESI⁺: calc'd for C₄₉H₅₀F₂N₈O₇:900.38 (M⁺). Found: 901.4 (M+H⁺).

Example FA

[1-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]1H-imidazol-2-yl}pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substituting 2-Methoxycarbonylamino-3-methyl-butyricacid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid.LCMS-ESI⁺: calc'd for C₄₇H₄₅F₂N₈O₆: 858.37 (M⁺). Found: 859.88 (M+H⁺).

Example FB

6-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester

6-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester (3.05 g, 84%) was prepared following the procedure for2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester, substituting5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-tert-butyl ester forPyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESC: calc'dfor C₂₆H₃₆BN₃O₄: 465.28 (M⁺). Found: 466.64 (M+H⁺).

[1-(6-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(6-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.10 g, 34%) was prepared following the procedure for[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substituting 2-Methoxycarbonylamino-3-methyl-butyricacid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid and6-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester for4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester. LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₆: 848.40 (M⁺). Found:849.96 (M+H⁺).

Example FC

[2-(6-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]hept-5-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

[2-(6-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]hept-5-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester (0.10 g, 44%) was prepared following the procedure for[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substituting6-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester for4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester. LCMS-ESI⁺: calc'd for C₅₁H₅₄N₈O₇: 890.41 (M⁺). Found:891.99 (M+H⁺).

Example FD

[1-(2-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-2-phenyl-acetyl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-2-phenyl-acetyl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.08 g, 28%) was prepared following the procedure for{2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester, substituting 2-Methoxycarbonylamino-3-methyl-butyricacid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid and6-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylicacid tert-butyl ester for2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylicacid tert-butyl ester. LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₆: 848.40 (M⁺).Found: 849.95 (M+H⁺).

Example FE

{2-[6-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-5-aza-spiro[2.4]hept-5-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester

{2-[6-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-5-aza-spiro[2.4]hept-5-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester (0.09 g, 33%) was prepared following the procedure for{2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester, substituting6-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-11H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylicacid tert-butyl ester for2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylicacid tert-butyl ester. LCMS-ESI⁺: calc'd for C₅₁H₅₄N₈O₇: 890.41 (M⁺).Found: 891.96 (M+H⁺).

Example FF

[1-(2-{5-[6-(4-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.05 g, 17%) was prepared following the procedure for{2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester, substituting 2-Methoxycarbonylamino-3-methyl-butyricacid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid.LCMS-ESI⁺: calc'd for C₄₇H₄₈F₂N₈O₆: 858.37 (M⁺). Found: 859.92 (M+H⁺).

Example FG

[1-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)pyrrolidin-2-yl]-3H-imidazol-4-yl}-napthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methoxy-propyl]-carbamicacid methyl ester

[1-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methoxy-propyl]-carbamicacid methyl ester (0.07 g, 23%) was prepared following the procedure for[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substituting 3-Methoxy-2-methoxycarbonylamino-butyricacid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid.LCMS-ESI⁺: calc'd for C₄₇H₄₈F₂N₈O₇: 874.36 (M⁺). Found: 875.90 (M+H⁺).

Example FH

[2-Methoxy-1-(6-{6-(5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamicacid methyl ester

[2-Methoxy-1-(6-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamicacid methyl ester (0.09 g, 29%) was prepared following the procedure for[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substituting 3-Methoxy-2-methoxycarbonylamino-butyricacid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid and6-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylicacid tert-butyl ester for2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylicacid tert-butyl ester. LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₇: 864.40 (M⁺).Found: 865.97 (M+H⁺).

Example FI

2-[7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of2-(7-Bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-carboxylicacid tert-butyl ester (2.00 g, 7.17 mmol) in Dioxane (19 mL) was added4,4,5,5,4′,4′,5′,5′-Octamethyl-2,2′-bi(1,3,2)dioxaborolane (1.82 g, 7.17mmol) and 1,1′-Bis(diphenylphosphino)ferrocenedichloride Palladium (0.18g, 0.24 mmol). The solution was degassed with argon for 5 min andheated, with stirring to 85° C. (external, oil bath) for 3 h. Thereaction was cooled to room temperature and diluted with EtOAc. Theprecipitate was filtered through celite and the filtrate wasconcentrated. The crude oil was purified by column chromatography (SiO₂,20→100% EtOAc (10% MeOH) in Hexanes) to provide2-[7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (1.82 g, 82%). LCMS-ESI⁺: calc'd for C₂₆H₃₆BN₃O₄:465.28 (M⁺). Found: 466.54 (M+H⁺).

[2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid tert-butyl ester

[2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2l]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid tert-butyl ester (0.04 g, 18%) was prepared following the procedurefor[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substitutingtert-Butoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid forMethoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid and2-[7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester for4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester. LCMS-ESI⁺: calc'd for C₅₄H₆₀N₈O₇: 932.46 (M⁺). Found:933.95 (M+H⁺).

Example FJ

4-(Carboxy-methoxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester

4-(Carboxy-methoxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester (1.2 g, 97%) was prepared following the procedure for2-Methoxycarbonylamino-2-phenyl-propionic acid, substituting4-(Amino-carboxy-methyl)-piperidine-1-carboxylic acid tert-butyl esterfor 2-Amino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd for C₁₄H₂₄N₂O₆:316.16 (M⁺). Found: 339.02 (M+Na⁺).

(2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-tert-butoxycarbonylpiperidin-4-yl-ethyl)-carbamicacid methyl ester

(2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-tert-butoxycarbonylpiperidin-4-yl-ethyl)-carbamicacid methyl ester (0.05 g, 20%) was prepared following the procedure for[2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substituting4-(Carboxy-methoxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-aceticacid and2-[7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester for4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester. LCMS-ESI⁺: calc'd for C₅₆H₆₃N₉O₈: 989.48 (M⁺). Found:991.11 (M+H⁺).

Example FK

[2-Oxo-1-phenyl-2-(2-{5-[6-(2-{1-[2-propionylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamicacid methyl ester

To a solution of[2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid tert-butyl ester (0.018 g, 0.020 mmol) in CH₂Cl₂ (0.25 mL) and MeOH(0.03 mL) was added HCl (in dioxanes, 4 M, 0.05 mL, 0.2 mmol). Thesolution was stirred at room temperature for 3 days and concentrated todryness. The resulting solid was dissolved in DMF (0.5 mL). DIPEA (0.02mL, 0.12 mmol) and Propionyl chloride (0.003 mL, 0.03 mmol) were added,and the reaction was stirred at room temperature for 1 h. The solutionwas then purified by preparative HPLC (Gemini, 15→60% MeCN in H₂O (0.1%TFA)) and lyophilized to provide to provide[2-Oxo-1-phenyl-2-(2-{5-[6-(2-{1-[2-propionylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamicacid methyl ester (0.01 g, 44%). LCMS-ESI⁺: calc'd for C₅₂H₅₆N₈O₆:888.43 (M⁺). Found: 890.07 (M+H⁺).

Example FL

[2-(2-{5[6-(2-{1-[2-(Cyclopropanecarbonyl-amino)-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-carbamicacid methyl ester

[2-(2-{5-[6-(2-{1-[2-(Cyclopropanecarbonyl-amino)-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-carbamicacid methyl ester (0.01 g, 38%) was prepared following the procedure for[2-Oxo-1-phenyl-2-(2-{5-[6-(2-{1-[2-propionylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamicacid methyl ester, substituting Cyclopropanecarbonyl chloride forPropionyl chloride. LCMS-ESI⁺: calc'd for C₅₃H₅₆N₈O₆: 900.43 (M⁺).Found: 902.07 (M+H⁺).

Example FM

(2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-piperidin-4-yl-ethyl)-carbamicacid methyl ester

To a solution of(2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-tert-butoxycarbonylpiperidin-4-yl-ethyl)-carbamicacid methyl ester (0.025 g, 0.025 mmol) in CH₂Cl₂ (0.25 mL) and MeOH(0.025 mL) was added HCl (in dioxane, 0.12 mL, 0.48 mmol). The solutionwas stirred at room temperature for 3 days and concentrated to dryness.The crude oil was purified by preparative HPLC (Gemini, 15→50% MeCN inH₂O (0.1% TFA)) and lyophilized to provide(2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-piperidin-4-yl-ethyl)-carbamicacid methyl ester (0.015 g, 66%). LCMS-ESI⁺: calc'd for C₅₁H₅₅N₉O₆:889.43 (M⁺). Found: 890.29 (M+H⁺).

Example FN

(1-(1-Methanesulfonyl-piperidin-4-yl)-2-{2-[7-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamicacid methyl ester

To a solution of(2-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-piperidin-4-yl-ethyl)-carbamicacid methyl ester (0.022 g, 0.025 mmol) in CH₂Cl₂ (0.5 mL) and DMF (0.5mL) was added DIPEA (0.025 mL, 0.14 mol) and Methanesulfonic anhydride(0.007 g, 0.04 mmol). The solution was stirred at room temperature for 1h and concentrated. The crude oil was purified by preparative HPLC(Gemini, 15-60% MeCN in H₂O (0.1% TFA)) and lyophilized to provide(1-(1-Methanesulfonyl-piperidin-4-yl)-2-{2-[7-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamicacid methyl ester (0.01 g, 46%). LCMS-ESI⁺: calc'd for C₅₂H₅₇N₉O₈S:967.41 (M⁺). Found: 969.19 (M+H⁺).

Example FO

3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester was prepared following the procedure for2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester, substituting2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester forPyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI⁺: calc'dfor C₂₆H₃₆BN₃O₄: 465.28 (M⁺). Found: 466.21 (M+H⁺).

[2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-ethyl]-carbamicacid methyl ester

To a solution of3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.25 g, 0.54 mmol) in CH₂Cl₂ (5 mL) and MeOH (0.5mL) was added HCl (in dioxane, 4 M, 1.35 mL, 5.40 mmol). The solutionwas stirred at room temperature for 2 h and concentrated to dryness. Theresulting solid was slurried in CH₂Cl₂ (5 mL) and DMF (1 mL).Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.15 g, 0.71mmol), COMU (0.25 g, 0.59 mmol), and DIPEA (0.50 mL, 0.59 mmol) wereadded, and the resulting solution was stirred at room temperature for 1h. The reaction was diluted with EtOAc and washed with saturated sodiumbicarbonate and brine. The aqueous layers were backextracted with EtOAc.The combined organic layers were dried over Na₂SO₄ and concentrated. Thecrude oil was purified by column chromatography (SiO₂, 10→100% EtOAc(10% MeOH) in Hexanes) to provide[2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-ethyl]-carbamicacid methyl ester (0.24 g, 79%). LCMS-ESI⁺: calc'd for C₃₀H₄₁BN₄O₆:564.31 (M⁺). Found: 565.40 (M+H⁺).

2-(5-{6-[4-(2-{2-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-2-aza-bicyclo[2.2.1]hept-3-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of[2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-ethyl]-carbamicacid methyl ester (0.24 g, 0.42 mmol) in DME (2.5 mL) was added2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.19 g, 0.43 mmol),Tetrakis(triphenylphosphine)Palladium (0.03 g, 0.02 mmol) and aqueouspotassium phosphate (2 M, 0.65 mL, 1.3 mmol). The solution was degassedwith argon for 15 min and heated to 80° C. for 18 h with stirring. Thesolution was cooled and concentrated. The crude oil was purified bycolumn chromatography (SiO₂, 30→100% EtOAc (10% MeOH) in Hexanes to 50%MeOH in EtOAc) to provide2-(5-{6-[4-(2-{2-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-2-azabicyclo[2.2.1]hept-3-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.26 g, 76%). LCMS-ESI⁺: calc'd for C₄₆H₅₃N₇O₆:799.41 (M⁺). Found: 800.4 (M+H⁺).

[2-(3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

To a solution of2-(5-{6-[4-(2-{2-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-2-aza-bicyclo[2.2.1]hept-3-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.26 g, 0.32 mmol) in CH₂Cl₂ (3.5 mL) and MeOH(0.2 mL) was added HCl (in dioxanes, 4 M, 1.6 mL, 6.4 mmol). Theresulting solution was stirred at room temperature for 2 h andconcentrated. The resulting solid was slurried in CH₂Cl₂ (3.5 mL) andDMF (0.5 mL). Methoxycarbonylamino-phenyl-acetic acid (0.08 g, 0.39mmol) and DIPEA (0.250 mL, 1.43 mmol) were added and the solution wascooled to 0° C. (external, ice bath). COMU (0.16 g, 0.36 mmol) was addedand the reaction was stirred at 0° C. for 3 h. The solution was dilutedwith CH₂Cl₂ and washed with saturated sodium bicarbonate and brine. Theaqueous layers were backextracted with CH₂Cl₂. The combined organiclayers were dried over Na₂SO₄ and concentrated. The crude oil waspurified by preparative HPLC (Gemini, 15→60% MeCN in H₂O (0.1% TFA)).The combined fractions were concentrated until the aqueous layerremained. A small amount of MeOH was added to make the solutionhomogenous before it was basified with saturated sodium bicarbonate. Theresulting precipitate was filtered, washed with H₂O, and dried in vacuoto provide[2-(3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester (0.21 g, 72%). LCMS-ESI⁺: calc'd for C₅₁H₅₄N₈O₇:890.41 (M⁺). Found: 891.95 (M+H⁺).

Example FP

[2-Methoxy-1-(3-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamicacid methyl ester

[2-Methoxy-1-(3-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamicacid methyl ester (0.18 g, 39%) was prepared following the procedure for[2-(3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substituting 3-Methoxy-2-methoxycarbonylamino-butyricacid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid.LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₇: 864.40 (M⁺). Found: 865.87 (M+H⁺).

Example FQ

3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylicacid tert-butyl ester

3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylicacid tert-butyl ester (0.16 g, 60%) was prepared following the procedurefor 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester, substituting2-Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester forPyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI⁺: calc'dfor C₁₉H₂₂BrN₃O₂: 403.09 (M⁺). Found: 404.76 (M+H⁺).

3-(5-{4′-[2-(2-tert-Butoxycarbonyl-2-aza-bicyclo[3.1.0]hex-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

To a solution of3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.19 g, 0.41 mmol) in DME (2.0 mL) was added3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylicacid tert-butyl ester (0.16 g, 0.41 mmol),Tetrakis(triphenylphosphine)Palladium (0.05 g, 0.04 mmol) and aqueouspotassium phosphate (2 M, 0.60 mL, 1.2 mmol). The solution was degassedwith argon for 15 min and heated to 80° C. for 18 h with stirring. Thesolution was cooled diluted with EtOAc and filtered. The filtrate waswashed with H₂O and brine. The organic layers were dried over Na₂SO₄ andconcentrated. The crude oil was purified by column chromatography (SiO₂,30→100% EtOAc (10% MeOH) in Hexanes to 80% MeOH in EtOAc). The desiredfractions were concentrated and combined with the filtered solid toprovide3-(5-{4′-[2-(2-tert-Butoxycarbonyl-2-aza-bicyclo[3.1.0]hex-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.17 g, 62%). LCMS-ESI⁺: calc'd for C₃₉H₄₆N₆O₄:662.36 (M⁺). Found: 663.39 (M+H⁺).

(1-{3-[5-(4′-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of3-(5-{4′-[2-(2-tert-Butoxycarbonyl-2-aza-bicyclo[3.1.0]hex-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.17 g, 0.25 mmol) in CH₂Cl₂ (3.0 mL) and MeOH(0.5 mL) was added HCl (in dioxane, 4 M, 2.0 mL, 8.0 mmol). The solutionwas stirred at room temperature for 2.5 h, then at 50° (external, oilbath) for 1 h. The solution was cooled and concentrated. The resultingsolid was slurried in CH₂Cl₂ (3.0 mL) and DMF (0.5 mL).2-Methoxycarbonylamino-3-methyl-butyric acid (0.12 g, 0.56 mmol), HATU(0.21 g, 0.54 mmol), and DIPEA (0.4 mL, 2.29 mmol) were added. Thesolution was stirred at room temperature for 1 h and concentrated. Thecrude oil was purified by preparative HPLC (Gemini, 15→50% MeCN in H₂O(0.1% TFA)). The combined fractions were concentrated until the aqueouslayer remained. A small amount of MeOH was added to make the solutionhomogenous before it was basified with saturated sodium bicarbonate. Theresulting precipitate was filtered, washed with H₂O, and dried in vacuoto provide(1-{3-[5-(4′-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.13 g, 64%). LCMS-ESI⁺: calc'd for C₄₃H₅₂N₈O₆:776.40 (M⁺). Found: 777.64 (M+H⁺).

Example FR

3-(7-Bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylicacid tert-butyl ester

To a solution of 2-Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid2-tert-butyl ester (0.08 g, 0.34 mmol) in CH₂Cl₂ (3.5 mL) was added6-Bromo-naphthalene-1,2-diamine (0.09 g, 0.041 mmol), HATU (0.16 g, 0.43mmol), and DIPEA (0.3 mL, 1.72 mmol). The resulting solution was stirredat room temperature for 1.5 h and diluted with EtOAc. The organic layerwas washed with H₂O and brine. The aqueous layers were backextractedwith EtOAc. The combined organic layers were dried over Na₂SO4 andseparated. The crude oil was purified by column chromatography (SiO₂,10→100% EtOAc (2% MeOH) in hexanes) to provide an oil that was dissolvedin AcOH (7.0 mL). The solution was stirred at 40° C. (external, oilbath) for 2 h. The solution was diluted with EtOAc and slowly basifiedwith saturated sodium bicarbonate and NaOH (2N). The organic layer wasseparated, dried over Na₂SO₄, and concentrated. The crude oil waspurified by column chromatography (SiO₂, 10→100% EtOAc (2% MeOH) inhexanes) to provide3-(7-Bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylicacid tert-butyl ester (0.15 g, 97%). LCMS-ESI⁺: calc'd for C₂₁H₂₂BrN₃O₂:427.09 (M⁺). Found: 428.35 (M+H⁺).

(1-{3-[7-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-1H-naphtho[1,2-d]imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(1-{3-[7-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-1H-naphtho[1,2-d]imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.13 g, 45%) was prepared following the procedure for(1-{3-[5-(4′-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester, substituting3-(7-Bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylicacid tert-butyl ester for3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylicacid tert-butyl ester. LCMS-ESI⁺: calc'd for C₄₅H₅₂N₈O₆: 800.40 (M⁺).Found: 801.73 (M+H⁺).

Example FS

[1-(2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester.[1-(2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, substituting 4-Methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₄₈H₅₂N₈O₇: 852.40 (M⁺). Found: 853.43 (M+H⁺).

Example FT

[1-(2-{5-[6-(4-{2-[4-Fluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[4-Fluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester.[1-(2-{5-[6-(4-{2-[4-Fluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, substituting 4-Fluoro-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₄₇H₄₉FN₈O₆: 840.38 (M⁺). Found: 841.45 (M+H⁺).

Example FU

[1-(2-{5-[6-(4-{2-[4-Fluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[4-Fluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester.[1-(2-{5-[6-(4-{2-[4-Fluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, substituting 4-Fluoro-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₄₇H₄₉FN₈O₆: 840.38 (M⁺). Found: 842.1 (M+H⁺).

Example FV

[1-(2-{5-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-fluoro-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-fluoro-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester.[1-(2-{5-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-fluoro-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, substituting 4-Fluoro-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester and Dimethylamino-phenyl-acetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₄₇H₅₁FN₈O₄: 810.40 (M⁺). Found: 811.4 (M+H⁺).

Example FW

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-methyl-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-methyl-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-methyl-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, substituting 4-Methyl-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₄₈H₅₂N₈O₆: 836.40 (M⁺). Found: 837.70 (M+H⁺).

Example FX

[1-(2-{5-[6-(4-{2-[4-Ethoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[4-Ethoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester.[1-(2-{5-[6-(4-{2-[4-Ethoxy-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, substituting 4-Ethoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₄₉H₅₄N₈O₇: 866.41 (M⁺). Found: 867.35 (M+H⁺).

Example FY

[1-(2-{5-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-ethoxy-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-ethoxy-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-1-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester.[1-(2-{5-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-ethoxy-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[1-(2-{5-[6-(4-{(2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, substituting 4-Ethoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester for Pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester and Dimethylamino-phenyl-acetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₄₉H₅₆N₈O₅: 836.44 (M⁺). Found: 837.80 (M+H⁺).

Example FZ

2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester.2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester was prepared following the procedure for2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester, substituting4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester forPyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.

Example GA

[1-(4-Methoxy-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(4-Methoxy-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester.[1-(4-Methoxy-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester was prepared following the procedure for[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, substituting2-{5-[6-(4-{2-[4-Methoxy-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester for2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester and Methoxycarbonylamino-phenyl-acetic acid for2-Methoxycarbonylamino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₄₈H₅₂N₈O₇: 852.40 (M⁺). Found: 853.46 (M+H⁺).

Example GB

Methyl(S)-1-((S)-2-(5-(4′-(2-((1R,3S,4S)-2-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

The title compound was prepared as described for{2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester, substituting (S)-benzyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate for(S)-benzyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl esterfor 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.LCMS-ESI⁺: calculated for C₄₅H₅₁N₈O₆: 799.4; observed [M+1]⁺: 799.4.

Example GC

Methyl(S)-1-((S)-2-(5-(4′-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

The title compound was prepared as described for{2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester, substituting (S)-benzyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate for(S)-benzyl2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate,2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester for4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester, andMethoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid forMethoxycarbonylamino-phenyl-acetic acid. LCMS-ESI⁺: calculated forC₄₄H₅₅N₈O₇: 807.4. observed [M+1]⁺: 807.4.

Example GD

Methyl(S)-1-((S)-2-(5-(6-(3-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

The title compound was prepared as described for[2-(3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]hept-2-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester, substituting 2-bromo-1-(3-bromophenyl)ethanone for1-(4-Bromo-phenyl)-2-chloro-ethanone, Pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester for 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid2-tert-butyl ester, and (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid.

LCMS-ESI⁺: calculated for C₄₄H₅₃N₈O₆: 789.4. observed [M+1]⁺: 789.6.

Example GE

2-6-Dibromo-3,4-dihydro-2H-naphthalen-1-one

6-Bromo-3,4-dihydro-2H-naphthalen-1-one (2.0 g) was dissolved in ether(80 mL), and Br₂ (455 μl) was added at 0° C. over 30 min. After dilutingwith ether (80 mL), the reaction mixture was washed with 10% Na₂SO₃,sat. NaHCO₃ and brine. After the solvent was removed, the crude materialwas used for the next step without further purification.

Pyrrolidine-1,2-dicarboxylic acid2-(6-bromo-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) ester 1-tert-butylester

The crude 2-6-dibromo-3,4-dihydro-2H-naphthalen-1-one andpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.15 g) weredissolved in MeCN (80 mL), and DIEA (2.55 mL) was added. The mixture wasstirred at 65° C. for overnight and diluted with ethyl acetate. Themixture was washed with 1 N HCl, NaHCO₃ and brine. After the solvent wasremoved, the resulting material was subjected to silica gelchromatography using effluent of 10-40% ethyl acetate and hexanes. Thefractions containing product were combined and the solvent was removedunder reduced pressure to provide pyrrolidine-1,2-dicarboxylic acid2-(6-bromo-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) ester 1-tert-butylester (1.54 g, 40% over 2 steps).

2-(7-Bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid2-(6-bromo-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl) ester 1-tert-butylester (1.54 g) and ammonium acetate (2.71 g) were suspended in toluene(35 mL). The reaction mixture was stirred at 110° C. for overnight andevaporated under reduced pressure and resulting residue was taken up inethyl acetate (100 mL). The organic phase was washed with saturatedsodium bicarbonate (1×150 mL) and dried over sodium sulfate. After thesolvent was removed, the resulting oil was subjected to silica gelchromatography using effluent of 60-90% ethyl acetate and hexanes. Thefractions containing product were combined and the solvent was removedunder reduced pressure to provide2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.05 g, 71%) as a pale brown solid. MS (ESI) m/z418.1 [M+H]⁺.

(1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Title compound was prepared according to the method employed to[1-(6-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2-methoxy-ethoxy)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester: MS (ESI) m/z 815.5 [M+H]⁺.

Methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

To(1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (13.0 mg, 0.016 mmol) in CH₂Cl₂ (1 mL) was added MnO₂(2.8 mg, 0.032 mmol). The reaction was stirred overnight then additionalMnO₂ (1.4 mg, 0.016 mmol) was added. After stirring for 3 hours, thereaction was filtered through a Whatman 0.45 mM PTFE filter. Thefiltrate was concentrated then purified by preparative reverse phaseHPLC (Gemini, 10 to 45% ACN/H₂O+0.1% TFA) to yield methyl(S)-1-((S)-2-(5-(6-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(6.3 mg, 48%). LCMS-ESI⁺: calculated for C₄₆H₅₃N₈O₆: 813.4. observed[M+1]⁺: 813.4.

Example GF

2-Bromo-3,5-dimethoxy-benzoic acid methyl ester

3,5-Dimethoxy-benzoic acid methyl ester (4.0 g) was dissolved in MeCN(28 mL), and NBS (4.4 g) was added at 0° C. After stirring at roomtemperature for 3 hours, saturated Na₂SO₃ (15 mL) was added. The mixturewas evaporated under vacuum and extracted with ether (1×, 500 mL). Afterthe solvent was removed, the crude material was subjected to silica gelchromatography using effluent of 10-40% ethyl acetate and hexanes. Thefractions containing product were combined and the solvent was removedunder reduced pressure to provide 2-bromo-3,5-dimethoxy-benzoic acidmethyl ester (5.2 g, 93%) as a clear oil.

4,6,4′,6′-Tetramethoxy-biphenyl-2,2′-dicarboxylic acid dimethyl ester

2-Bromo-3,5-dimethoxy-benzoic acid methyl ester (5.2 g) was dissolved inDMF (16 mL), and Cu powder (2.4 g) was added. After stirring at 150° C.for 3 days, the mixture was filtered and evaporated under vacuum. Thecrude material was subjected to silica gel chromatography using effluentof 30-60% ethyl acetate and hexanes. The fractions containing productwere combined and the solvent was removed under reduced pressure toprovide 4,6,4′,6′-tetramethoxy-biphenyl-2,2′-dicarboxylic acid dimethylester (2.5 g, 68%) as a clear oil.

(6′-Hydroxymethyl-4,6,2′,4′-tetramethoxy-biphenyl-2-yl)-methanol

4,6,4′,6′-tetramethoxy-biphenyl-2,2′-dicarboxylic acid dimethyl ester(2.5 g) was dissolved in THF (96 mL), and 1M LiAlH₄ in THF (9.6 mL) wasadded. After stirring at room temperature for overnight, the mixture wasquenched with water and 2N HCl (24 mL) was added. The mixture wasevaporated under vacuum and partitioned with DCM (300 mL) and water (200mL). The organic layer was dried over Na₂SO₄ and crystallized with DCMto provide(6′-hydroxymethyl-4,6,2′,4′-tetramethoxy-biphenyl-2-yl)-methanol (1.7 g,77%) as a pale blue white triclinic crystals.

6,6′-Bis-bromomethyl-2,4,2′,4′-tetramethoxy-biphenyl

(6′-hydroxymethyl-4,6,2′,4′-tetramethoxy-biphenyl-2-yl)-methanol (779mg) was dissolved in DCM (5.8 mL), and PBr₃ (527 uL) was slowly added at0° C. After stirring at 0° C. for 30 min. and at room temperature for 1hour, H₂O (40 mL) was added. The mixture was extracted with ether (1×,50 mL). After the solvent was removed, the crude material was subjectedto silica gel chromatography using effluent of 10-40% ethyl acetate andhexanes. The fractions containing product were combined and the solventwas removed under reduced pressure to provide6,6′-bis-bromomethyl-2,4,2′,4′-tetramethoxy-biphenyl (700 mg, 65%) as athick oil.

6,6′-Bis-bromomethyl-biphenyl-2,4,2′,4′-tetraol

6,6′-bis-bromomethyl-2,4,2′,4′-tetramethoxy-biphenyl (685 mg) wasdissolved in DCM (3.0 mL), and 1M BBr₃ in DCM (16.4 mL) was slowlyadded. After stirring for 2 days, the mixture was poured on to ice andconcentrated. The crude material was used for the next step without afurther purification.

5-10-Dihydro-chromeno[5,4,3-cde]chromene-2,7-diol

The crude 6,6′-bis-bromomethyl-biphenyl-2,4,2′,4′-tetraol was dissolvedin DMF (30 mL), and Cs₂CO₃ (1.9 g) was added. After stirring at roomtemperature for 1 hour, the mixture was partitioned with 1 N HCl (100mL) and ethyl acetate (100 mL), and extracted with ethyl acetate (3×,100 mL). After the solvent was removed, the crude material was subjectedto silica gel chromatography using effluent of 10-15% methanol and DCM.The fractions containing product were combined and the solvent wasremoved under reduced pressure to provide5-10-dihydro-chromeno[5,4,3-cde]chromene-2,7-diol (301 mg, 84%) as awhite solid.

Trifluoro-methanesulfonic acid7-trifluoromethanesulfonyloxy-5,10-dihydro-chromeno[5,4,3-cde]chromen-2-ylester

5-10-Dihydro-chromeno[5,4,3-cde]chromene-2,7-diol (290 mg) was dissolvedin DCM (12 mL), and Tf₂O (1.2 mL) and pyridine (969 uL) were added.After stirring at room temperature for overnight, the mixture waspartitioned with 2 N HCl (50 mL) and DCM (50 mL), and washed with 2 NHCl (2×50 mL) and saturated sodium bicarbonate (1×50 mL). After thesolvent was removed, the resulting oil was subjected to silica gelchromatography using effluent of 0-30% ethyl acetate and hexanes. Thefractions containing product were combined and the solvent was removedunder reduced pressure to provide trifluoro-methanesulfonic acid7-trifluoromethanesulfonyloxy-5,10-dihydro-chromeno[5,4,3-cde]chromen-2-ylester (472 mg, 78%) as an off-white solid.

2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene

A solution of trifluoro-methanesulfonic acid7-trifluoromethanesulfonyloxy-5,10-dihydro-chromeno[5,4,3-cde]chromen-2-ylester (5.18 g, 10.2 mmol), bis(pinacolato)diboron (10.39 g, 41 mmol) andtriethylamine (7.11 mL, 51 mmol) 1,4-dioxanes (100 mL) was degassed withargon for fifteen minutes. To this solution was added PdCl₂(dppf) (1.49g, 2.04 mmol) and the reaction was heated to 90° C. overnight. Themixture was cooled to room temperature and concentrated. The crude solidwas suspended in MeOH and stirred for 30 minutes, filtered andthoroughly rinsed with methanol to yield2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene(3.21 g, 68%) as a yellow solid.

(2S,2′S)-tert-butyl2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

A mixture of2,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene(1.50 g, 3.25 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.60 g, 11.4mmol), tetrakis(triphenylphosphine)palladium(0) (751 mg, 0.65 mmol),PdCl₂(dppf) (476 mg, 0.65 mmol), 2M aqueous potassium carbonate (9.8 mL,19.2 mmol), DMSO (33 mL) and 1,4-dioxanes (33 ml mL) was degassed withargon for 15 minutes. The reaction was then heated to 110° C. for 2hours. Upon completion, the reaction was cooled to room temperature thenpoured into a saturated NaHCO₃ solution. The solution was extracted withEtOAc 2× then the organic phase was washed with brine. The resultingcrude material was purified by flash column chromatography (0 to 10%MeOH/EtOAc) to afford (2S,2′S)-tert-butyl2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(1.58 mg, 68%).

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

A solution of (2S,2′S)-tert-butyl2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(90 mg, 0.13 mmol), concentrated HCl (1.0 mL) and ethanol (2 mL) washeated to 60° C. for one hour. The reaction was concentrated and placedon the high-vac overnight. The crude amine was dissolved indimethylformamide (2.2 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (58 mg, 0.33 mmol),HATU (104 mg, 0.27 mmol) and 4-methylmorpholine (0.075 mL, 0.65 mmol).The reaction was stirred at room temperature for two hours. Uponcompletion, the reaction was quenched with formic acid then purified bypreparative reverse phase HPLC (Gemini, 10 to 45% ACN/H₂O+0.1% TFA) toyield dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(64 mg, 62%). LCMS-ESI⁺: calculated for C₄₂H₅₁N₈O₈: 795.4. observed[M+1]⁺: 795.8.

Example GF-2

dimethyl(2S,2′S)-1,1′-((2R,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

Dimethyl(2S,2′S)-1,1′-((2R,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate:The title compound was prepared as in dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate,using racemic tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate instead of(S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.The diastereomeric products were separated by preparative reverse phaseHPLC (Gemini, 10 to 45% ACN/H₂O+0.1% TFA). LCMS-ESI⁺: calculated forC₄₂H₅₁N₈O₈: 795.4. observed [M+1]⁺: 795.8.

Dimethyl (2S,2′S)-1,1′-((2R,2′R)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

The title compound was prepared as in dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate,using racemic tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate instead of(S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.The diastereomeric products were separated by preparative reverse phaseHPLC (Gemini, 10 to 45% ACN/H₂O+0.1% TFA). LCMS-ESI⁺: calculated forC₄₂H₅₁N₅O₈: 795.4. observed [M+1]⁺: 795.8.

Example GG

Pyrrolidine-1,2-dicarboxylic acid2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester

2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone (20.01g, 61 mmol) and BocProline OH (12.51g, 58.1 mmol) were suspended in acetonitrile (290 mL).Triethylamine (8.9 mL, 63.9 mmol) was added, and the solution wasallowed to stir at room temperature overnight. Upon completion, thereaction was concentrated in vacuo and purified by normal phasechromatography (0-40% Ethyl acetate in Hexanes) to givePyrrolidine-1,2-dicarboxylic acid2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl](assumed 61 mmol).

2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid2-[2-(6-bromo-naphthalen-2-yl)-2-oxo-ethyl] (61 mmol) and ammoniumacetate (610 mmol) were suspended in toluene (300 mL) and heated toreflux for 18 hours. Solid precipitated during the course of thereaction and it was filtered off and washed with ethyl acetate to give2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (13.3g, 50% over two steps) as a tan solid.LCMS-ESI⁺: calc'd for C₂₂H₂₄BrN₃O₂: 441.11 and 443.10 (M⁺). Found:443.93 (M+H⁺).

(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (6.4g, 14.4 mmol) was added HCl in dioxane (36 mL,144 mmol). The suspension was allowed to stir at room temperature forthree hours. Upon completion by LCMS, the reaction was concentrated todryness and the crude product (assumed 14.4 mmol) was suspended indichloromethane. 2-Methoxycarbonylamino-3-methyl-butyric acid (3.8g,21.7 mmol) and solid potassium phosphate (28.94 mmol) were added to theslurry. HATU (6.88g, 18.08 mL) was added and the reaction was stirred atroom temperature for 18 hours. Upon completion, the crude reaction wasfiltered through a sintered glass funnel. The supernate was concentratedin vacuo and purified by normal phase silica gel chromatography (20-70%Ethyl acetate (with 10% MeOH) in Hexanes) to give(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (7.14g, >90% yield) as a thick oil. LCMS-ESI⁺: calc'dfor C₂₄H₂₇BrN₄O₃: 498.13 (M⁺). Found: 499.96 (M+H⁺).

4-Methylene-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

This compound was made using the same procedure used to make[2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester using 4-Methylene-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester. LCMS-ESI⁺: calc'd for C₂₅H₃₄BN₃O₄: 451.26 (M⁺).Found: 452.33 (M+H⁺).

2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester

4-Methylene-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-3carboxylicacid tert-butyl ester (0.20g, 0.443 mmol),(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.170g, 0.341 mmol) and potassium phosphate (2M, 0.51mL, 1.023 mmol) were suspended in 1,2-dimethoxyethane (3.4 mL) andsparged with argon gas for 30 minutes. Palladium tetrakistriphenylphosphine (0.039g, 0.034 mmol) was added and the reactionmixture was capped and heated to 80° C. with a preheated external oilbath and a JChem temperature controller. Upon completion, the reactionwas filtered through diatomaceous earth, washed with ethyl acetate,diluted in ethyl acetate, washed with bicarb. The organic phases weredried with sodium sulfate, filtered and concentrated. The crude productwas purified by reverse phase HPLC (10-40% acetonitrile:water; 0.1%formic acid modifier), and lyophilized giving2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester (0.032g, 12% yield) as a white solid. LCMS-ESI⁺:calc'd for C₄₃H₄₉N₇O₅: 743.38 (M⁺). Found: 744.31 (M+H⁺).

Example GH

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was made using the same procedure used to make[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester (0.032g, 0.043 mmol) to give[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.002g, 5.6% yield) was a white solid. LCMS-ESI⁺:calc'd for C₄₈H₅₀N₈O₆: 834.39 (M⁺). Found: 835.80 (M+H⁺).

Example GI

(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

This compound was made using the same procedure used to make2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester using 4-Methylene-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (3.81g, 16.76 mmol) to give(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (5.76g, 83% yield). LCMS-ESI⁺: calc'd forC₂₅H₂₇BrN₄O₃: 510.13 (M⁺). Found: 511.63 (M+H⁺).

2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

This compound was synthesized using the same method used to make2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester using(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-methylene-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.200g, 0.391 mmol) and2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.223g, 0.508 mmol) to give2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.040g, 0.054 mmol). LCMS-ESI⁺: calc'd forC₄₃H₄₉N₇O₅: 743.38 (M⁺).

Found: 744.73 (M+H⁺).

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was made using the same procedure used to make[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, giving[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.005g, 2% yield) as a white solid.

LCMS-ESI⁺: calc'd for C₄₈H₅₀N₈O₆: 834.39 (Me). Found: 835.32 (M+H⁺).

Example GJ

Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid

Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid was prepared usingthe procedure used to prepare(2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid usingAmino-(2-methoxy-phenyl)-acetic acid. LCMS-ESI⁺: calc'd for C₁₁H₁₃NO₅:239.08 (M⁺). Found: 239.94 (M+H⁺).

Example GK

{1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-4-methylene-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

This compound was synthesized using the same method used to synthesize[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using Methoxycarbonylamino-(2-methoxy-phenyl)-aceticacid (0.020g, 0.082 mmol) giving{1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-4-methylene-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester (0.011g, 23% yield) as a white solid. LCMS-ESI⁺:calc'd for C₄₉H₅₂N₈O₇: 864.40 (M⁺). Found: 865.35 (M+H⁺).

Example GL

[2-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

This compound was synthesized using the same procedure used tosynthesize(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)}-2-methyl-propyl)-carbamicacid methyl ester from2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.469g, 1.13 mmol) usingMethoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.295 g, 1.356mmol).[2-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester (0.264g, 43% yield). LCMS-ESI⁺: calc'd forC₂₆H₂₉BrN₄O₄: 540.14 (M⁺). Found: 542.08 (M+H⁺).

3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

This compound was synthesized using the same procedure as[2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester using 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylicacid 2-tert-butyl ester. LCMS-ESI⁺: calc'd for C₂₆H₃₆BN₃O₄: 465.28 (M⁺).Found: 466.41 (M+H⁺).

3-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

This compound was synthesized using the same procedure used to make2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester using[2-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-yl}-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester (0.150g, 0.277 mmol) and3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.155g, 0.332 mmol) to give3-(5-{4-[6-(2-{I-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.106g, 48% yield). LCMS-ESI⁺: calc'd forC₄₆H₅₃FN₇O₆: 799.41 (M⁺). Found: 800.85 (M+H⁺).

[2-(2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-2-phenyl-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamicacid methyl ester

This compound was synthesized using the same procedure used to make[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-4-methylene-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester, giving the title compound (0.070g, 59% yield) as awhite solid. LCMS-ESI⁺: calc'd for C₅₁H₅₄N₈O₇: 890.41 (M⁺). Found:891.47 (M+H⁺).

Example GM

3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

This compound was synthesized using the procedure used to synthesize2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester using(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.200g, 0.400 mmol) and3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-11H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.224g, 0.48 mmol) giving3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.192g, 63% yield). LCMS-ESI⁺: calc'd forC₄₄H₅₁N₇O₅: 757.40 (M⁺). Found: 758.78 (M+H⁺).

[1-(2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-2-phenyl-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was synthesized using the procedure used to synthesize[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using Methoxycarbonylamino-phenyl-acetic acid (0.079g,0.380 mmol) giving the title compound (0.100g, 46.6% yield) as a whitesolid. LCMS-ESI⁺: calc'd for C₄₉H₅₂N₈O₆: 848.40 (M⁺). Found: 849.50(M+H⁺).

Example GN

[2-Methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamicacid methyl ester

This compound was synthesized using the procedure used to make[2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester using 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylicacid 2-tert-butyl ester. LCMS-ESI⁺: calc'd for C₂₈H₃₉BN₄O₅: 522.30 (M⁺).Found: 523.31 (M+H⁺).

2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

This compound was synthesized using the procedure used to make2-(5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester using2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.200g, 0.452 mmol) and[2-Methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamicacid methyl ester (0.283g, 0.543 mmol) to give2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.242g, 71% yield). LCMS-ESI⁺: calc'd forC₄₄H₅₁N₇O₅: 757.40 (M⁺). Found: 758.50 (M+H⁺).

[1-(3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was synthesized using the procedure used to make[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using Methoxycarbonylamino-phenyl-acetic acid (0.100g,0.479 mmol) to give the title compound (0.124g, 46% yield). LCMS-ESI⁺:calc'd for C₄₉H₅₂N₈O₆: 848.40 (M⁺). Found: 849.97 (M+H⁺).

Example GO

[2-Methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamicacid methyl ester

This compound was synthesized using the procedure used to make[2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester using 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylicacid 2-tert-butyl ester. LCMS-ESI⁺: calc'd for C₂₈H₃₉BN₄O₅: 522.30 (M⁺).Found: 523.31 (M+H⁺).

2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

This compound was synthesized using the procedure used to make2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester using2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.124g, 0.279 mmol) and[2-Methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamicacid methyl ester (0.219g, 0.419 mmol) to give2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.154g, 73% yield). LCMS-ESI⁺: calc'd forC₄₄H₅₁N₇O₅: 757.40 (M⁺). Found: 758.42 (M+H⁺).

[1-(2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was synthesized using the procedure used to make(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester using2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (0.154g, 0.203 mmol) giving the tile compound(0.041g, 24% yield) as a white solid. LCMS-ESI⁺: calc'd for C₄₆H₅₄N₈O₆:814.42 (M⁺). Found: 815.49 (M+H⁺).

Example GP

3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

This compound was synthesized using the procedure used to make2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester using(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.161 g, 0.322 mmol) and3-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.195g, 0.419 mmol) to give3-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.133g, 46% yield). LCMS-ESI⁺: calc'd forC₄₄H₅₁N₇O₅: 757.40 (M⁺). Found: 758.26 (M+H⁺).

[1-(2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-2-phenyl-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was synthesized using the procedure used to make[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using Methoxycarbonylamino-phenyl-acetic acid (0.047g,0.224 mmol) to give[1-(2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-2-phenyl-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.044g, 34.8% yield). LCMS-ESI⁺: calc'd forC₄₉H₅₂N₈O₆: 848.40 (M⁺). Found: 849.96 (M+H⁺).

Example GQ

2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

This compound was made using the same procedure used to make2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester using2-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester. LCMS-ESI⁺: calc'd for C₄₂H₄₉N₇O₅: 731.38 (M⁺).Found: 732.81 (M+H⁺).

[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester in DCM (4.76 mL) and MeOH(0.238 mL) was added HClin dioxane(4N, 1.25 mL, 5 mmol). The solution was allowed to stir atroom temperature for approximately 2 hours. Upon completion, the crudereaction mixture was concentrated in vacuo. The resulting solid wassuspended in DCM (mL) and tert-Butoxycarbonylamino-phenyl-acetic acidwas added. Solid potassium phosphate (0.318g, 1.5 mmol) was added andthe suspension was cooled to 0° C. (external, ice/water bath). COMU wasadded at 0° C. and the slurry was allowed to stir at 0° C. for one hour.Upon completion, the crude reaction mixture was filtered through asyringe filter, and concentrated. The resulting slurry was diluted inDMF and purified by reverse phase HPLC (10-40% acetonitrile:water; 0.1%formic acid modifier), and lyophilized giving[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.305g, 61%) as a white solid. LCMS-ESI⁺: calc'd forC₅₀H₅₆N₈O₆: 864.43 (M⁺). Found: 865.77 (M+H⁺).

[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.211g, 0.244 mmol) was dissolved in DCM (2.439 mL).HCl in dioxane (4N, 0.610 mL, 2.44 mmol) was added at room temperatureand the resulting solution was stirred for approximately one hour. Uponcompletion, the reaction was concentrated in vacuo to giving[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester as a white solid (assumed 0.244 mmol) that was usedwithout further purification in subsequent reactions. LCMS-ESI⁺: calc'dfor C₄₅H₄₈N₈O₄: 764.43 (M⁺). Found: 765.31 (M+H⁺).

Example GR

{2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.085g, 0.097 mmol), (Tetrahydro-pyran-4-yl)-aceticacid (0.017g, 0.117 mmol), and N-methylmorpholine (0.032 mL, 0.292 mmol)were suspended in DMF(0.972 mL) at room temperature. Solid HATU (0.055g,0.146 mmol) was added and the suspension was allowed to stir at roomtemperature overnight. Upon completion, the reaction was quenched with asmall amount of formic acid and purified by reverse phase HPLC (10-45%acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving{2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester (0.062g, 62%) as a white solid. LCMS-ESI⁺: calc'd forC₅₂H₅₈N₈O₆: 890.45 (M⁺). Found: 892.4 (M+H⁺).

Example GS

{1-[2-(5-{6-[4-(2-{1-[2-(2-Dimethylamino-acetylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

This compound was prepared using the procedure used to prepare{2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester using Dimethylamino-acetic acid (0.018g, 0.172 mmol)to provide{1-[2-(5-{6-[4-(2-{1-[2-(2-Dimethylamino-acetylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester (0.106g, >99%) as a white solid. LCMS-ESI⁺: calc'd forC₄₉H₅₅N₉O₅: 849.43 (M). Found: 850.60 (M+H⁺).

Example GT

Isopropoxycarbonylamino-phenyl-acetic acid

Amino-phenyl-acetic acid (0.505g, 2.44 mmol) was dissolved in THF (7 mL)and cooled to 0° C. in an external ice/brine bath. Aqueous sodiumhydroxide (12.5M, 0.47 mL, 5.856 mmol) and isopropyl chloroformate (0.23mL, 2.948 mmol) were added at 0° C. Upon completion of the addition, thesolution was removed from the ice bath and allowed to warm to roomtemperature, and stirred. After 18 hours, the crude reaction mixture wasadjusted to pH 1 with 1N HCl and extracted twice with diethyl ether. Thecombined organic layers were washed with brine, dried with magnesiumsulfate and concentrated to give Isopropoxycarbonylamino-phenyl-aceticacid as an off-white solid. LCMS-ESI⁺: calc'd for C₁₂H₁₅NO₄: 237.10(M⁺). Found: 238.05 (M+H⁺).

Example GU

[1-(2-{5-[6-(4-{2-[1-(2-Isopropoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was prepared using the procedure used to prepare[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using Isopropoxycarbonylamino-phenyl-acetic acid(0.066g, 0.281 mmol) to provide{1-[2-(5-{6-[4-(2-{1-[2-(2-Fluoro-phenyl)-2-methoxycarbonylamino-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester (0.025g, 16%) as a white solid. LCMS-ESI⁺: calc'd forC₄₉H₅₄N₈O₆: 850.42 (M⁺). Found: 851.83 (M+H⁺).

Example GV

[2-Methyl-1-(2-{5-[6-(4-{2-[1-(2-phenyl-2-propionylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester

[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.05g, 0.057 mmol) was suspended in THF(0.572 mL).Upon addition of DIPEA (0.050 mL, 0.286 mmol), the slurry partiallyclarified. Propionyl chloride (0.005 mL, 0.057 mmol) was added at roomtemperature and the reaction was allowed to sit at room temperatureovernight. Upon completion, the reaction was quenced with a small amountof formic acid and purified by reverse phase HPLC (10-45%acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving[2-Methyl-1-(2-{5-[6-(4-{2-[1-(2-phenyl-2-propionylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (0.008g, 17%) as a white solid. LCMS-ESI⁺: calc'd forC₄₈H₅₂N₈O₈: 820.41 (M⁺). Found: 821.51 (M+H⁺).

Example GW

(2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid

Amino-(2-fluoro-phenyl)-acetic acid (0.5g, 2.44 mmol) was dissolved inTHF (7 mL) and cooled to 0° C. in an external ice/brine bath. Aqueoussodium hydroxide (12.5M, 0.47 mL, 5.856 mmol) and methyl chloroformate(0.23 mL, 2.948 mmol) were added at 0° C. Upon completion of theaddition, the solution was removed from the ice bath and allowed to warmto room temperature, and stirred. After 18 hours, the crude reactionmixture was adjusted to pH 1 with 1N HCl and extracted twice withdiethyl ether. The combined organic layers were washed with brine, driedwith magnesium sulfate and concentrated to give(2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid as an off-whitesolid. LCMS-ESI⁺: calc'd for C₁₀H₁₀FNO₄: 227.06 (M⁺). Found: 228.17(M+H⁺).

Example GX

{1-[2-(5-{6-[4-(2-{1-[2-(2-Fluoro-phenyl)-2-methoxycarbonylamino-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

This compound was prepared using the procedure used to prepare[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using (2-Fluoro-phenyl)-methoxycarbonylamino-aceticacid (0.061g, 0.269 mmol) to provide{1-[2-(5-{6-[4-(2-{1-[2-(2-Fluoro-phenyl)-2-methoxycarbonylamino-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester (0.012g, 8%) as a white solid. LCMS-ESI⁺: calc'd forC₄₇H₄₉FN₈O₆: 840.38 (M⁺). Found: 841.86 (M+H⁺).

Example GY

Methoxycarbonylamino-o-tolyl-acetic acid

Methoxycarbonylamino-o-tolyl-acetic acid was prepared using theprocedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-aceticacid using Amino-o-tolyl-acetic acid. LCMS-ESI⁺: calc'd for C₁₁H₁₃NO₄:223.08 (M⁺). Found: 223.94 (M+H⁺).

Example GZ

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was prepared using the procedure used to prepare[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using Methoxycarbonylamino-o-tolyl-acetic acid(0.072g, 0.332 mmol) to provide[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-o-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.047g, 31.4%) as a white solid. LCMS-ESI⁺: calc'dfor C₄₈H₅₂N₈O₆: 836.40 (M⁺). Found: 837.86 (M+H⁺).

Example HA

Methoxycarbonylamino-m-tolyl-acetic acid

Methoxycarbonylamino-m-tolyl-acetic acid was prepared using theprocedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-aceticacid using Amino-m-tolyl-acetic acid. LCMS-ESI⁺: calc'd for C₁₁H₁₃NO₄:223.08 (M⁺). Found: 223.90 (M+H⁺).

Example HB

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-m-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was prepared using the procedure used to prepare[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using Methoxycarbonylamino-m-tolyl-acetic acid(0.046g, 0.206 mmol) to provide[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-m-tolyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.039g, 34%) as a white solid. LCMS-ESI⁺: calc'd forC₄₈H₅₂N₈O₆: 836.40 (M⁺). Found: 837.91 (M+H⁺).

Example HC

Methoxycarbonylamino-(3-methoxy-phenyl)-acetic acid

Methoxycarbonylamino-(3-methoxy-phenyl)-acetic acid was prepared usingthe procedure used to prepare(2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid usingAmino-(3-methoxy-phenyl)-acetic acid. LCMS-ESI⁺: calc'd for C₁₁H₁₃NO₅:239.08 (M⁺). Found: 239.94 (M+H⁺).

Example HD

{1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(3-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

This compound was prepared using the procedure used to prepare[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using Methoxycarbonylamino-(3-methoxy-phenyl)-aceticacid (0.049g, 0.206 mmol) to provide{1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(3-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester (0.006g, 5%) as a white solid.

LCMS-ESI⁺: calc'd for C₄₈H₅₂N₈O₇: 852.40 (M⁺). Found: 853.33 (M+H⁺).

Example HE

2-Methoxycarbonylamino-2-phenyl-propionic acid

2-Methoxycarbonylamino-2-phenyl-propionic acid was prepared using theprocedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-aceticacid using 2-Amino-2-phenyl-propionic acid. LCMS-ESI⁺: calc'd forC₁₁H₁₃NO₄: 223.08 (M⁺). Found: 223.96 (M+H⁺).

Example HF

[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was prepared using the procedure used to prepare[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using 2-Methoxycarbonylamino-2-phenyl-propionic acid(0.068g, 0.308 mmol) to provide[1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.035g, 20%) as a white solid. LCMS-ESI⁺: calc'd forC₄₈H₅₂N₈O₆: 836.40 (M⁺). Found: 837.92 (M+H⁺).

Example HG

(Ethyl-methoxycarbonylamino)-phenyl-acetic acid

(Ethyl-methoxycarbonylamino)-phenyl-acetic acid was prepared using theprocedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-aceticacid using Ethylamino-phenyl-acetic acid. LCMS-ESI⁺: calc'd forC₁₂H₁₅NO₄: 237.10 (M⁺). Found: 238.03 (M+H⁺).

Example HH

{1-[2-(5-{6-[4-(2-{1-[2-(Ethyl-methoxycarbonylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

This compound was prepared using the procedure used to prepare[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using (Ethyl-methoxycarbonylamino)-phenyl-acetic acid(0.097g, 0.410 mmol) to provide{1-[2-(5-{6-[4-(2-{1-[2-(Ethyl-methoxycarbonylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester (0.120g, 52%) as a white solid. LCMS-ESI⁺: calc'd forC₄₉H₅₄N₈O₆: 840.38 (M⁺). Found: 851.91 (M+H⁺).

Example HI

2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

This compound was synthesized using the procedure used to make2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylicacid tert-butyl ester using2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.641g, 1.449 mmol) and(2-Methyl-1-{2-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester (1.06g, 2.029 mmol) to give2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.812g, 74% yield) as a solid. LCMS-ESI⁺: calc'dfor C₄₄H₅₁N₇O₅: 757.40 (M⁺). Found: 758.75 (M+H⁺).

(1-{2-[7-(6-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

This compound was synthesized using the procedure used to make[1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.400g, 0.528 mmol) to give(1-{2-[7-(6-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.180g, 38% yield). LCMS-ESI⁺: calc'd for C₅₂H₅₈N₈O₆:890.45 (M⁺). Found: 891.88 (M+H⁺).

(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

This compound was synthesized using the procedure used to make[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester using(1-{2-[7-(6-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.180g, 0.202 mmol) to give the title compound(0.160, >99% yield). LCMS-ESI⁺: calc'd for C₄₇H₅₀N₈O₄: 790.40 (M⁺).Found: 791.39 (M+H⁺).

Example HJ

[2-Methyl-1-(2-{7-[6-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester

This compound was prepared using the same procedure used to make{2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester using(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.020g, 0.022 mmol) to give[2-Methyl-1-(2-{7-[6-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (0.003g, 15% yield). LCMS-ESI⁺: calc'd for C₅₄H₆₀N₈O₆:916.46 (M⁺). Found: 917.44 (M+H⁺).

Example HK

{2-Methyl-1-[2-(7-{6-[2-(1-{2-phenyl-2-[(tetrahydro-pyran-4-carbonyl)-amino]-acetyl}-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester

This compound was prepared using the same procedure used to make{2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester using(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.046g, 0.051 mmol) to give{2-Methyl-1-[2-(7-{6-[2-(1-{2-phenyl-2-[(tetrahydro-pyran-4-carbonyl)-amino]-acetyl}-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester (0.061g, >99% yield). LCMS-ESI⁺: calc'd forC₅₃H₅₈N₈O₆: 902.45 (M⁺). Found: 904.02 (M+H⁺).

Example HL

[1-(2-{7-[6-(2-{1-[2-(2-Hydroxy-2-methyl-propionylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was prepared using the same procedure used to make{2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester using(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.048g, 0.053 mmol) to give[1-(2-{7-[6-(2-{1-[2-(2-Hydroxy-2-methyl-propionylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.0145g, 31% yield). LCMS-ESI⁺: calc'd forC₅₁H₅₆N₈O₆: 876.43 (M⁺). Found: 878.01 (M+H⁺).

Example HM

[2-Methyl-1-(2-{7-[6-(2-{1-[2-(2-morpholin-4-yl-acetylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester

This compound was prepared using the same procedure used to make{2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester using(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.043 g, 0.050 mmol) to give[2-Methyl-1-(2-{7-[6-(2-{1-[2-(2-morpholin-4-yl-acetylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (0.021g, 45% yield). LCMS-ESI⁺: calc'd for C₅₃H₅₉N₉O₆:917.46 (M⁺). Found: 918.54 (M+H⁺).

Example HN

(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

This compound was synthesized from2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-naphtho[1,2-d]imidazol-7-yl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.590 g, 0.78 mmol) using the three step sequenceused to make[1-(2-{5-[6-(4-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester from2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester, giving the title compound (0.277 mmol, 35% yieldover three steps). LCMS-ESI⁺: calc'd for C₄₇H₄₈N₈O₄: 788.38 (M⁺). Found:790.1 (M+H⁺).

Example HO

[1-(2-{7-[6-(2-{1-[2-(2-Hydroxy-2-methyl-propionylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

This compound was prepared using the same procedure used to make{2-Methyl-1-[2-(5-{6-[4-(2-{1-[2-phenyl-2-(2-tetrahydro-pyran-4-yl-acetylamino)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester using(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.247g, 0.227 mmol) to give[1-(2-{7-[6-(2-{1-[2-(2-Hydroxy-2-methyl-propionylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (0.074g, 31% yield). LCMS-ESI⁺: calc'd for C₅₁H₅₄N₈O₆:874.42 (M⁺). Found: 875.5 (M+H⁺).

Example HP

Carbonic acid 4-nitro-phenyl ester oxetan-3-yl ester

A solution of Oxetan-3-ol (0.100g, 1.35 mmol) and pyridine (0.13 mL,1.62 mmol) in THF (2.5 mL) was cooled to 0° C. with an external icebath, stirring. A solution of 4-Nitrophenyl chloroformate (0.299g, 1.485mmol) in THF (2 mL) was added at 0° C. and the solution was allowed towarm to room temperature. The crude reaction was purified by normalphase silica gel (0-100% ethyl acetate:hexanes) chromatography to giveCarbonic acid 4-nitro-phenyl ester oxetan-3-yl ester. LCMS-ESI⁺: calc'dfor C₁₀H₉NO₆: 239.04 (M⁺). Found: 239.97 (M+H⁺).

[2-Methyl-1-(2-{7-[6-(2-{1-[2-(oxetan-3-yloxycarbonylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester

(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.200g, 0.22 mmol) was dissolved in acetonitrile (2.2mL). DIPEA (0.155 mL, 0.8905 mmol) and Carbonic acid 4-nitro-phenylester oxetan-3-yl ester (0.059g, 0.244 mmol) was added, and the solutionwas allowed to stir for about three hours. Upon completion, the crudeproduct was purified by reverse phase HPLC (10-50% acetonitrile:water;0.1% formic acid modifier), and lyophilized giving[2-Methyl-1-(2-{7-[6-(2-{1-[2-(oxetan-3-yloxycarbonylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (0.61g, 31% yield). LCMS-ESI⁺: calc'd for C₅₁H₅₂N₈O₇:888.40 (M⁺). Found: 889.86 (M+H⁺).

Example HQ

{2-Methyl-1-[2-(7-{6-[2-(1-{2-[(morpholine-4-carbonyl)-amino]-2-phenyl-acetyl}-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-1H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester

This compound was synthesized using the same procedure used to make[2-Methyl-1-(2-{5-[6-(4-{2-[1-(2-phenyl-2-propionylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester using(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.200g, 0.222 mmol) to give{2-Methyl-1-[2-(7-{6-[2-(1-{2-[(morpholine-4-carbonyl)-amino]-2-phenyl-acetyl}-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-1H-naphtho[1,2-d]imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester (0.036g, 18% yield). LCMS-ESI⁺: calc'd for C₅₂H₅₅N₉O₆:901.43 (M⁺). Found: 902.60 (M+H⁺).

Example HR

1-(5-bromo-2-iodobenzyloxy)-6-methoxynaphthalene

To a solution of 6-methoxynaphthalen-1-ol (4.45 g, 25.6 mmol),(5-bromo-2-iodophenyl)methanol (8.0 g, 25.6 mmol) and triphenylphosphine(7.4 g, 28.2 mmol) in tetrahydrofuran (128 mL) at 0° C. was addeddiisopropyl azodicarboxylate (5.54 mL, 28.2 mmol). The reaction wasallowed to warm to room temperature overnight. After 15 hours, moretriphenylphosphine (1.3 g, 5 mmol) and diisopropyl azodicarboxylate(0.99 mL, 5 mmol) were added and the reaction was stirred at roomtemperature. After 24 hours, the reaction was concentrated andrecrystallized from CH₂Cl₂ and hexanes to yield1-(5-bromo-2-iodobenzyloxy)-6-methoxynaphthalene (7.82 g, 65%). Themother liquor was purified by flash column chromatography to yield moreproduct (790 mg, 6.5%).

8-bromo-2-methoxy-6H-dibenzo[c,h]chromene

A mixture of 1-(5-bromo-2-iodobenzyloxy)-6-methoxynaphthalene (5.0 g,10.7 mmol) and sodium acetate (2.64 g, 32.1 mmol) in dimethylformamide(100 mL) was degassed with a stream of argon for 15 minutes.PdCl₂(PPh₃)₂ was added and the reaction was heated to 110° C. After 16hours the reaction was diluted with ethyl acetate, washed with water andbrine, dried (Na₂SO₄) and concentrated. The resulting residue waspurified by flash column chromatography to yield8-bromo-2-methoxy-6H-dibenzo[c,h]chromene (1.29 g, 35%).

8-bromo-6H-dibenzo[c,h]-chromen-2-ol

Pyridine hydrochloride (4.4 g, 37.8 mmol) was heated to 190° C.8-bromo-2-methoxy-6H-dibenzo[c,h]chromene (1.29 g, 3.8 mmol) was addedand the reaction was stirred at 190° C. After four hours, the reactionwas cooled to room temperature and diluted with water. A precipitateformed which was collected by filtration and purified by flash columnchromatography to yield 8-bromo-6H-dibenzo[c,h]-chromen-2-ol (697 mg,56%).

8-bromo-6H-dibenzo[c,h]chromen-2-yl trifluoromethanesulfonate

To a solution of 8-bromo-6H-dibenzo[c,h]-chromen-2-ol (697 mg, 2.1 mmol)and pyridine (0.23 mL, 2.8 mmol) in dichloromethane (25 mL) at 0° C. wasadded trifluoromethanesulfonic anhydride (0.39 mL, 2.3 mmol). Afterstirring for 2 hours, the reaction was poured into 1M aqueous HClsolution. The organic phase was separated and the aqueous phase wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated. The crude material waspurified by flash column chromatography to yield8-bromo-6H-dibenzo[c,h]chromen-2-yl trifluoromethanesulfonate (889 mg,91%).

2-bromo-1-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)ethanone

A solution of 8-bromo-6H-dibenzo[c,h]chromen-2-yltrifluoromethanesulfonate (780 mg, 1.7 mmol) andtributyl(1-ethoxyvinyl)stannane (0.86 mL, 2.6 mmol) in dimethylformamidewas degassed with a stream of argon for 15 minutes. PdCl₂(dppe) (50 mg,0.086 mmol) was added and the reaction was stirred at room temperature.After 30 hours, water (1 mL) and N-bromosuccinimide (756 mg, 4.2 mmol)were sequentially added to the reaction. After stirring for 2.5 hours atroom temperature the reaction was diluted with dichloromethane. Theorganics were washed with 5% aqueous LiCl solution, saturated aqueousNaHCO₃ solution, and brine. After the organic layer was dried (Na₂SO₄)and concentrated, the crude material was recrystallized fromdichloromethane and hexanes to yield2-bromo-1-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)ethanone (518 mg, 57%).

(S)-1-benzyl 2-(2-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate

To a mixture of 2-bromo-1-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)ethanone(518 mg, 1.2 mmol) and(S)-1-(benzyloxycarbonyl)-pyrrolidine-2-carboxylic acid (449 mg, 1.8mmol) in dimethylformamide (12 mL) was added triethylamine (0.25 mL, 1.8mmol). After stirring for 2 hours at room temperature, the reaction wasdiluted with 5% aqueous LiCl solution. The aqueous phase was extractedtwice with ethyl acetate. The combined organics were washed with 1Maqueous HCl solution, saturated aqueous NaHCO₃ solution and brine. Afterthe organic layer was dried (Na₂SO₄) and concentrated, the crudematerial was purified by flash column chromatography to yield(S)-1-benzyl 2-(2-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (620 mg, 86%).

(S)-benzyl2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-1-benzyl2-(2-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-2-oxoethyl)pyrrolidine-1,2-dicarboxylate (641 mg, 1.1 mmol) and ammonium acetate(823 mg, 10.7 mmol) in toluene (11 mL) was vigorously refluxed. After 8hours, the reaction was cooled to room temperature and poured intowater. The aqueous phase was extracted twice with ethyl acetate. Thecombined organic layers were washed with saturated aqueous NaHCO₃ andbrine, dried (Na₂SO₄) and concentrated. The crude material was purifiedby flash column chromatography to yield (S)-benzyl2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(541 mg, 87%).

Methyl(S)-1-((S)-2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of (S)-benzyl2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(485 mg, 0.84 mmol), hydrogen bromide (33% in acetic acid, 1 mL) anddichloromethane (2 mL) was stirred at room temperature for one hour. Thereaction was concentrated, suspended in toluene, sonicated for oneminute and re-concentrated. The resulting residue was suspended inmethanol, sonicated for one minute and concentrated. The resultingresidue was suspended in diethyl ether and the solids collected byfiltration. This crude amine was dissolved in dimethylformamide (7 mL).To this solution were added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (192 mg, 1.1 mmol),HATU (418 mg, 1.1 mmol) and N-methylmorpholine (0.24 mL, 2.2 mmol). Thereaction was stirred at room temperature for one hour, and then dilutedethyl acetate. The organic layer was washed with 5% aqueous LiClsolution, saturated aqueous NaHCO₃ solution and brine, then dried(Na₂SO₄) and concentrated. The crude material was purified by flashcolumn chromatography to yield methyl(S)-1-((S)-2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(466 mg, 92%).

(S)-tert-butyl2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]-chromen-8-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of methyl(S)-1-((S)-2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(466 mg, 0.77 mmol), bis(pinacolato)diboron (235 mg, 0.93 mmol) andpotassium acetate (227 mg, 2.3 mmol) in dioxane (4 mL) was degassed witha stream of argon for fifteen minutes. To this mixture was addedPdCl₂(dppf) (56 mg, 0.08 mmol) and the reaction was heated to 90° C.After 14 hours, the mixture was cooled to room temperature. To thereaction was added (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (341 mg, 1.1mmol), 2M aqueous potassium carbonate solution (1.54 mL, 3.1 mmol) andDMSO (3.9 mL). The reaction was degassed with a stream of argon forfifteen minutes. Tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.08mmol) was added and the reaction was heated to 90° C. After 4.5 hours,the reaction was poured into water. The aqueous phase was extractedtwice with ethyl acetate. The combined organic layers were washed withbrine, dried (Na₂SO₄) and concentrated. The crude material was purifiedby flash column chromatography to yield (S)-tert-butyl2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]-chromen-8-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(145 mg, 25%).

Methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of (S)-tert-butyl2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]-chromen-8-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(80 mg, 0.10 mmol), dioxanes (1 mL), methanol (1 mL), and 4M HCl indioxane (0.07 mL, 0.28 mmol) was stirred at room temperature. Thereaction was thoroughly concentrated after 24 hours.

The resulting residue was dissolved in a 4:1dichloromethane:dimethylformamide solution (2.5 mL). To this solutionwas added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (27 mg, 0.13mmol) and COMU (64 mg, 0.15 mmol) and the reaction was cooled to 0° C.Diisopropylethylamine (0.035 mL, 0.20 mmol) was added and the reactionwas stirred at 0° C. for one hour. The reaction was quenched by theaddition of formic acid (0.05 mL) and thoroughly concentrated. Theresulting residue was purified by preparative reverse phase HPLC(Gemini, 10 to 60% ACN/H₂O+0.1% HCO₂H), followed by a second preparativereverse phase HPLC (Gemini, 10 to 60% ACN/H₂O+0.1% TFA) to yield methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(47 mg, 52%). LCMS-ESI⁺: calculated for C₄₈H₅₀N₈O₇: 850.96. observed[M+1]⁺: 851.91.

Example HS

methyl(2S)-1-((2S)-2-(5-(8-(2-((2S)-1-(2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(2S)-1-((2S)-2-(5-(8-(2-((2S)-1-(2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:This compound was made in an analogous manner to methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (R)-2-(dimethylamino)-2-phenylacetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amidecoupling. LCMS-ESI⁺: calculated for C₄₈H₅₂N₈O₅: 820.41. observed [M+1]⁺:821.25.

Example HT

methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:This compound was made in an analogous manner to methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amidecoupling. LCMS-ESI⁺: calculated for C₄₇H₅₄N₈O₈: 858.98. observed [M+1]f:860.02.

Example HU

methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate

Methyl(S-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate:This compound was made in an analogous manner to methyl(S)-1-((S)-2-(5-(8-(2-((5)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (S)-2-(methoxycarbonylamino)butanoic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amidecoupling. LCMS-ESI⁺: calculated for C₄₇H₄₈N₃O₇: 836.93. observed [M+1]⁺:837.63.

Example HV

methyl(S)-2-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Methyl(S)-2-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate:This compound was made in an analogous manner to methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-6H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amidecoupling. LCMS-ESI⁺: calculated for C₅₀H₅₂N₈O₈: 893.00. observed[M+1-1]⁺: 894.07.

Example HW

methyl(2S,3R)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate

Methyl(2S,3R)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate:This compound was made in an analogous manner to methyl(S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amidecoupling. LCMS-ESI⁺: calculated for C₄₈H₅₀N₈O₈: 866.96. observed [M+1]⁺:867.96.

Example HX

(S)-2-benzyl 1-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate

To a stirring solution of a mixture of(S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (2.85 g,12.43 mmol) and potassium carbonate (4.33 g, 24.87 mmol) in anhydrousN,N-dimethylformamide (60 mL) was added benzyl bromide (4.25 g, 24.87mmol). The mixture was stirred at room temperature overnight.

The resulting crude mixture was diluted with ethylacetate and theorganic layer was washed with 10% sodium carbonate and brine. Theorganic layer was dried over sodium sulfate and volatiles were removedin-vacuo. The residue was purified on normal phase column. (2.82 g,71%).

(S)-benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride

To a stirring solution of (S)-2-benzyl 1-tert-butyl4-oxopyrrolidine-1,2-dicarboxylate (2.82 g, 8.8 mmol) in anhydroustetrahydrofuran (44 mL) was added 4N HCl in 1,4-dioxane (9.3 mL) at roomtemperature. The mixture was stirred for 18 hours at room temperature.The product was then three times with tolune on rotovap to dryness toremove all the excess acid and further dried on a high vacuum overnightand used as is in the next step. Quantative yield.

(S)-Benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate

(S)-Benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride (1.92 g, 8.8mmol), the acid (in this case(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid) (1.84 g, 10.56 mmol)and HATU (5.02 g, 13.2 mmol) were weighed out in a round bottom flaskand dissolved in anhydrous DMF (44 mL). To this mixture was added DIPEA(6.82g, 52.8 mmol) at room temperature and the mixture was stirred for 2h. The crude mixture was diluted with EtOAc and washed respectively withbrine, 10% Na₂CO₃ and brine again, and the mixture was dried over MgSO₄,after filtration the mixture was concentrated down on rotovap. Theresidue was then purified on normal phase chromatography. (2.45 g, 74%).

(S)-benzyl7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate

(S)-benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate(2.45 g, 6.51 mmol) in a round bottom flask was dissolved in anhydroustoluene (200 mL) and p-toluene sulfonic acid monohydride (124 mg, 0.1mmol) and ethylene glycol (808 mg, 13.02 mmol) were added and themixture was refluxed for 18 hours, removing the generated byproductwater with a Dean-Stark apparatus. The crude mixture was then dilutedwith ethyl acetate and washed, respectively, with 10% citric acid,saturated ammonium chloride, 10% sodium carbonate and finally withbrine. The organic layers were combined and dried over sodium sulfateand concentrated down on rotovap. The crude residue was then purified onnormal phase column chromatography with 5% MeOH/DCM. (2.3 g, 84%)

(S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylicacid

(S)-benzyl7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate(2.3 g, 5.47 mmol) was dissolved in ethyl alcohol (55 mL) and underArgon charged with 10% Pd/C (585 mg, 0.55 mmol) in a round bottom flask.The flask was then sealed with a rubber septa and the air was removed byvacuum and replaced with H₂ from a balloon. This process repeated threetimes and the mixture was stirred under H₂ atmosphere for 18 hours. Theresulting mixture was then passed through a celite plug and concentrateddown on rotovap. (1.76 g, 98%).

(S)-2-(4-bromophenyl)-2-oxoethyl7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate

Title compound was prepared according to the method employed to prepare(S)-2-(4-bromophenyl)-2-oxoethyl5-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-azaspiro[2.4]heptane-6-carboxylate(2.07g, 74%)

Methyl(S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Title compound was prepared according to the method employed to preparemethyl(S)-1-((S)-6-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate(1.64 g, 82.2%)

Example HY

(S)-tert-butyl2-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-butyl2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(150 mg, 0.296 mmol) and methyl(S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate(174 mg, 0.355 mmol) were weighed out in a microwave vessel anddissolved in 1,4-dioxane (3 mL), followed by 2M potassium carbonate (444uL, 0.888 mmol) and Pd(dppf)Cl₂ (21 mg, 0.03 mmol). The mixture wassonicated for 2 minutes and then bubbled with nitrogen gas for 3 min todegas. The vessel was sealed and the content was heated in microwave at110° C. for 30 min. The crude reaction mixture was then diluted withEtOAc and washed twice with brine and saturated NaHCO₃ and once withbrine again and dried over MgSO₄. The crude solution was then filteredand concentrated down. (233 mg, 99%).

Example HZ

Methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate

In a flask, (S)-tert-butyl2-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(233 mg, 0.296 mmol) was dissolved in a (2:1) mixture of 1,4-dioxane (6ml) and methanol (3 mL) and to this solution was added 4N HCl/Dioxane(740 uL). The mixture was stirred at room temperature overnight. Thereaction mixture was then concentrated down and dissolved in dioxane andconcentrated down to dryness again and finally suspended in diethyletherand concentrated down do dryness to obtain a beige color powderquantitatively as 3 HCl salt. The product used as-is in the next step.

Example IA

(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

Methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamateas 3HCl salt (200 mg, 0.24 mmol),(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (60 mg, 0.288 mmol),and COMU (154 mg, 0.36 mmol) were all weighed out in a scintillationvial and anhydrous N,N-dimethylformamide (2.4 mL) was added and withoutstirring to this mixture was then added DIPEA (124 mg, 0.96 mmol) andthe mixture was sonicated to dissolve all the reactants as quickly aspossible. The mixture was then stirred for 2 h at room temperature. Thecrude mixture was diluted with EtOAc and washed with brine, 10% Na₂CO₃,brine and the organic layer was dried over MgSO₄. The filtrate wasconcentrated down and the residue was purified by normal phase columnchromatography (5% MeOH/DCM). MS (ESI) m/z 881.84 [M+H]⁺. (95 mg, 45%).

Example IB

(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(diethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

Title compound was prepared according to the method employed to prepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3HCl salt. MS (ESI) m/z 879.82 [M+H]⁺. (53 mg, 50%).

Example IC

(S)-tert-butyl2-(7-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

Methyl(S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate(100 mg, 0.197 mmol), bis(pinacolato)diboron (51 mg, 0.2 mmol),potassium acetate (58 mg, 0.591 mmol), and Pd(dppf)Cl₂ (15 mg, 0.02mmol) were all weighed out in a glass pressure vessel and anhydrous1,4-Dioxane (1 mL) was added. The mixture was bubbled with nitrogen gasfor about 5 min. The vessel was then capped and sealed and heated in anoil bath at 95° C. overnight with continuous stirring. The reactionvessel was cooled down to room temperature and (S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (83mg, 0.29 mmol), 2M K₂CO₃ (296 uL), and Pd(PPh₃)₄ (23 mg, 0.02 mmol) wereall added along with 1 mL of DMSO or 1,4-dioxane and the mixture wasbubbled with nitrogen gas for 5 minutes. The vessel, again, was capped,sealed and placed in an oil bath at 100° C. for 4 hours. The resultingcrude mixture was diluted with ethyl acetate and washed, respectively,with brine, 10% Na₂CO₃, 10% citric acid, saturated solution of NH₄Cl,and brine. The organic layer was then dried over Na₂SO₄ and thevolatiles were removed on rotovap. The residue was purified on normalphase chromatography. (71 mg, 47%).

Example ID

Methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(2-((S)-pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3.HCl salt

Same procedure was used as that of the synthesis of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate.(75 mg, 100%)

Example IE

(2S,3R)-3-methoxy-1-((S)-2-(7-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare (S)-benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate,except that methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(2-((S)-pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3× HCl salt and (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acidwere used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylatehydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS(ESI) m/z 838.73 [M+H]⁺. (45 mg, 54%).

Example IF

(S)-1-((S)-2-(S-(6-(4-(2-((S)-7-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

Title compound was prepared according to the method employed to prepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(2S)-1-(2-(5-(6-(4-(2-((S)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate3× HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-1-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-11H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 881.91 [M+H]⁺. (137 mg, 38%).

Example IG

(R)-2-((S)-2-(5-(4-(6-(2-((S)-7-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazo-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

Title compound was prepared according to the method employed to prepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-2-oxo-2-((S)-8-(5-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3× HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3× HCl salt. MS (ESI) m/z 923.83 [M+H]⁺. (73 mg, 77%).

Example IH

R)-2-((S)-2-(5-(4-(6-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

Title compound was prepared according to the method employed to prepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3× HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3× HCl salt. MS (ESI) m/z 881.90 [M+H]⁺. (14 mg, 16%).

Example II

(S)-Methyl 4-oxopyrrolidine-2-carboxylate HCl salt

The title compound was prepared in quantative yield according to themethod employed to prepare methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate.

(S)-1-benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate

(S)-Methyl 4-oxopyrrolidine-2-carboxylate HCl salt (9.4 g, 52.6 mmol)was dissolved in 1,4-dioxane (210 mL) and a solution ofpotassiumbicarbonate (13.2 g, 131.5 mmol) in DI-water (70 mL) was addedat 0° C., followed by slow addition of benzylchloroformate (15 mL, 105.2mmol). The mixture was then let warm up to room temperature and it wasstirred overnight. The resulting crude mixture was concentrated down asmuch as possible on the rotovap and it was diluted with EtOAc and washedtwice with saturated NaHCO3 and 10% citric acid and once with saturatedNaHCO3 again and then with brine. The organic layer was dried overNa2SO4 and after filtration it was concentrated down on rotovap. Thecrude product was then purified on normal phase column chromatography(15% EtOAc/Hexanes). (14.6 g, 100%)

(S)-7-(Benzyloxycarbonyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylicacid

(S)-1-Benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (7.96 g, 28.71mmol) was dissolved in toluene (300 mL) and to it was added ethyleneglycol (17.82 g, 287.1 mmol) and p-toluene sulfonic acid monohydrate(546 mg). The flask that was equipped with a Dean-Stark apparatus withthis mixture in it was stirred in a 120° C. oil bath overnight.

Upon the completion of the reaction the intermediate formed was theethylene glycol ester instead of methyl ester due totrans-esterification. This intermediate was concentrated down onrotovap. The residue was taken up in MeOH (300 mL) and stirred inpresence of solid K2CO3 (7.94 g, 57.42 mmol) overnight at roomtemperature to convert the ethylene glycol ester to methyl ester. Afterconfirming the formation of methyl ester by LCMS and TLC, 1M LiOH (55mL) was added to the mixture and it was then stirred at room temperaturefor 3 h. All the volatiles were removed on rotovap and the residue wastaken up in toluene and concentrated down to dryness on rotovap and thiswas repeated three times. The resulting residue was further dried onhigh vacuum pump overnight.

The residue was taken up in DI-water and to it was added EtOAc and theorganic layer was separated. The organic layer was checked for theabsence of desired product. The water layer was then acidified using 2NHCl (about 70 mL) to adjust the pH to 5. Product was then extracted withEtOAc three times. Organic layers were combined washed with brine anddried over MgSO4 and further dried on high vacuum pump. (5.94 g, 67%).

Example IJ

(S)-benzyl8-(2-amino-4-bromophenylcarbamoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate

Title compound was prepared in quantative yield according to the methodemployed to make6-(2-Amino-5-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester and6-(2-Amino-4-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester, substituting(S)-5-(benzyloxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid with(S)-7-(benzyloxycarbonyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylicacid (357 mg, 99%).

(S)-benzyl8-(6-bromo-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate

Title compound was prepared according to the method employed to make6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester (276 mg, 80%).

(S)-Benzyl8-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate

The title compound was prepared according to the method employed toprepare (S)-tert-butyl2-(7-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(377 mg, 77%).

(S)-tert-butyl2-(5-(7-(2-((S)-1,4-dioxa-7-azaspiro[4.4]nonane-8-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-Benzyl8-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate(375 mg, 0.46 mmol) was dissolved in ethyl acetate (10 mL) and to it wasadded triethyl amine (140 mg, 1.38 mmol), followed by 10% Pd/C(Pearlman's catalyst)(196 mg, 0.09 mmol). The flask was purged withhydrogen gas three times by applying vacuum and purging hydrogen gasfrom a balloon and the mixture was stirred overnight at roomtemperature. The crude product was filtered through a 0.2 micron Nylonfilter member and the filtrate was concentrated down on rotovap. (229mg, 73%).

(S)-tert-butyl2-(5-(9,9-difluoro-7-(2-((S)-7-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

Title compound was prepared according to the method employed to prepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester. (47 mg, 34%).

Methyl(R)-2-((S)-8-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-2-oxo-1-phenylethylcarbamate3× HCl Salt

Title compound was prepared in quantative yield according to the methodemployed for making(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate.

Example IK

(R)-2-((S)-8-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare (S)-benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate,except that(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid andmethyl(R)-2-((S)-8-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-2-oxo-1-phenylethylcarbamateas 3HCl salt and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidwere used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylatehydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS(ESI) m/z 972.29 [M+H]⁺. (27.6 mg, 53%).

Example IL

(S)-2-((S)-8-(6-(9,9-difluoro-7-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

Title compound was prepared according to the method employed to prepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-2-((S)-8-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3× HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 972.54 [M+H]⁺. (30 mg, 43%).

Example IM

(S)-2-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-2-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3× HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 939.91 [M+H]⁺. (102 mg, 57%).

Example IN

(R)-2-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare (S)-benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate,except that methyl (R)-2-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamate3 HCl salt and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidwere used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylatehydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS(ESI) m/z 939.92 [M+H]⁺. (34 mg, 23%).

Example IO

(R)-2-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-1-((2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl (2S,3R)-1-((S)-2-(5-(7-(2-((1R,3S,4R)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 913.69 [M+H]⁺. (93 mg, 57%).

Example IP

(2S,3R)-1-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(2S,3R)-1-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 913.74 [M+H]⁺. (91.4 mg, 56%).

Example IQ

(R)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-1-((S)-8-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate3 HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 929.83 [M+H]⁺. (90 mg, 63%).

Example IR

(S)-1-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

(S)-8-(5-(7-(2-((1R,3S,4R)-2-Azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane4HCl salt (227 mg, 0.375 mmol), HATU (456 mg, 1.2 mmol), and(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (171 mg, 0.975 mmol)were all weighed out in a flask and dissolved in anhydrous DMF (3.75mL), followed by addition of DIPEA (485 mg, 3.75 mmol). The mixture wasstirred at room temperature overnight. The crude mixture was dilutedwith EtOAc and washed with brine, saturated sodium bicarbonate, brine,and dried over MgSO4. After filtration and concentration the residue wasfirst purified on normal phase column (5% MeOH/DCM) and then on prepHPLC. MS (ESI) m/z 921.89 [M+H]⁺. (72 mg, 21%).

Example IS

(R)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-2-((S)-2-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 914.51 [M+H]⁺. (86.2 mg, 53%).

Example IT

(R)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-1-((S)-2-(5-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 872.50 [M+H]⁺. (97.5 mg, 59%).

Example IU

(S)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare (S)-benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate,except that methyl(S)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3HCl salt was used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylatehydrochloride. MS (ESI) m/z 879.88 [M+H]⁺. (122 mg, 52%).

Example IV

(S)-1-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare (S)-benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate,except that methyl(S)-1-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate3HCl salt and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidwere used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylatehydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS(ESI) m/z 879.90 [M+H]⁺. (105.8 mg, 50%).

Example LW

(S)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-1-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3 HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 913.94 [M+H]⁺. (77.4 mg, 24%).

Example IX

(S)-1-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-1-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 871.95 [M+H]⁺. (174 mg, 53%).

Example IY

(R)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanamido)-2-methylpropyl)-1H-imidazol-4-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-1-((S)-1-(4-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-2-methylpropylamino)-3-methyl-1-oxobutan-2-ylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 873.92 [M+H]⁺. (62 mg, 37%).

Example IZ

(R)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetamido)-2-methylpropyl)-1H-imidazol-4-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-2-((S)-1-(4-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-2-methylpropylamino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 915.94 [M+H]⁺. (52 mg, 32%).

Example JA

Methyl(S)-2-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-(diethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

The title compound was prepared according to the method employed toprepare (S)-benzyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate,except that(R)-2-(diethylamino)-2-phenyl-1-((S)-2-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)ethanone4HCl salt and(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidwere used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylatehydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS(ESI) m/z 863.81 [M+H]⁺. (34 mg, 39%).

Example JB

(R)-2-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)thiazolidin-3-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-thiazolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate4HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 841.83 [M+H]⁺. (25 mg, 12%).

Example JC

(S)-1-((S)-2-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)thiazolidin-3-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

Methyl(R)-2-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(155 mg, 0.29 mmol), methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)thiazolidin-3-yl)butan-2-ylcarbamate(195 mg, 0.37 mmol), Pd(dppf)Cl2 (43 mg, 0.058 mmol) and 2M K2CO3 (320uL, 0.64 mmol) were all dissolved in 1,4-dioxane (1.5 mL) and themixture was bubbled with nitrogen gas for 5 minutes. The vessel wascapped, sealed and placed in an oil bath at 95° C. for 3 hours.

The resulting crude mixture was diluted with ethyl acetate and washed,respectively, with brine, 10% Na₂CO₃, 10% citric acid, saturatedsolution of NH₄Cl, and brine. The organic layer was then dried overNa₂SO₄ and the volatiles were removed on rotovap. The residue waspurified on normal phase chromatography. (19 mg, 8%).

Example JD

(R)-tert-butyl4-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)oxazolidine-3-carboxylate

The title compound was prepared according to the method employed toprepare (S)-Tert-butyl2-(7-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate,except that, respectively, methyl(S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateand (R)-tert-butyl4-(5-(4-bromophenyl)-1H-imidazol-2-yl)oxazolidine-3-carboxylate wereused instead of methyl(S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate(100 mg, 0.197 mmol), bis(pinacolato)diboron and (S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate. MS(ESI) m/z 734.91 [M+H]⁺. (110 mg, 45%).

Example JE

(R)-Benzyl1-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate3HCl salt and(R)-2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylicacid were used instead of, respectively, methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt (R)-2-(methoxycarbonylamino)-2-phenylacetic acid. MS (ESI)m/z 841.83 [M+H]⁺. (135 mg, 99%).

Example JF

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-1,2,3,4-tetrahydroisoquinoline-1-carbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

(R)-Benzyl1-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(137 mg, 0.148 mmol) was dissolved in ethyl alcohol (5 mL) and underArgon charged with 10% Pd/C (79 mg, 0.074 mmol) in a round bottom flask.The flask was then sealed with a rubber septa and the air was removed byvacuum and replaced with H2 from a balloon. This process repeated threetimes and the mixture was stirred under H2 atmosphere for 18 hours. Theresulting mixture was then passed through a celite plug and concentrateddown on rotovap. (117 mg, 99%).

Example JG

Methyl(S)-3-methyl-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-1,2,3,4-tetrahydroisoquinoline-1-carbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(135 mg, 0.17 mmol), acetic acid (1.7 mL), zinc dust (111 mg, 1.7 mmol),and formaldehyde were all mixed in round bottom flask and stirred atroom temperature overnight. The crude mixture was filtered through acelite plug and the filtrate was concentrated down to dryness onrotovap. The residue was then taken up in EtOAc and washed with 10%Na2CO3 and brine and dried over MgSO4. The filtrate was thenconcentrated down and the residue was purified on reverse phase HPLC.(13 mg, 10%). MS (ESI) m/z 805.77 [M+H]⁺.

Example JH

(2S,3R)-3-Methoxy-1-((S)-2-(7-(6-(2-((1R,3S,4S)-2-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl (2S,3R)-1-((S)-2-(7-(6-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-11H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 889.43 [M+H]⁺. (100 mg, 43%).

Example JI

(S)-2-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-2-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)thiazolidin-3-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that, respectively, methyl(S)-2-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamateand methyl (S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamatewere used instead of methyl(R)-2-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamateand methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)thiazolidin-3-yl)butan-2-ylcarbamate.MS (ESI) m/z 831.68 [M+H]⁺. (75 mg, 66%).

Example JJ

(S)-2-((S)-2-(7-(6-(2-((1R,3S,4S)-2-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl (S)-2-((S)-2-(7-(6-(2-((1R,3 S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 915.83 [M+H]⁺. (44 mg, 60%).

Example JK

(R)-2-((S)-2-(7-(6-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl (S)-2-oxo-2-((1R,3S,4S)-3-(5-(6-(2-((S)-pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 915.83 [M+H]⁺. (59 mg, 88%).

Example JL

(R)-2-((S)-2-(7-(6-(2-((1R,3S,4S)-2-((2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

The title compound was prepared according to the method employed toprepare(S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, except that methyl (2S,3R)-3-methoxy-1-oxo-1-((1R,3S,4S)-3-(5-(6-(2-((S)-pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate3HCl salt was used instead of methyl(S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate3 HCl salt. MS (ESI) m/z 889.79 [M+H]⁺. (56 mg, 79%).

Example JM

(S)-2-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

(1R,3 S,4S)-tert-Butyl3-(5-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(235 mg, 0.45 mmol), bis(pinacolato)diboron (234 mg, 0.92 mmol),potassium acetate (115 mg, 1.17 mmol), and Pd(dppf)Cl₂ (18 mg, 0.02mmol) were all weighed out in a glass pressure vessel and DME (4.5 mL)was added. The mixture was bubbled with nitrogen gas for about 5 min.The vessel was then capped and sealed and heated in an oil bath at 90°C. overnight with continuous stirring. The reaction vessel was cooleddown to room temperature and all volatiles were removed under reducedpressure and the resulting oil was subjected to silica gelchromatography with an eluent of ethyl acetate and hexane at a gradientof 0-50% with an ISCO column (12 g silica gel). The fractions containingproduct were combined and the solvent was removed under reduced pressureto provide 1R,3S,4S)-tert-butyl3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(230 mg, 90%).

To 1R,3S,4S)-tert-butyl3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(97 mg, 0.17 mmol), methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(67 mg, 0.18 mmol), Pd(PPh₃)₄ (10 mg, 0.009 mmol). DME (1.7 mL) wasadded and followed by 0.7 mL 1M NaHCO3 aqueous solution. The reactionwas purged with Ar and heated to 120° C. at microwave synthesizer for0.5 hour. The reaction was cooled to room temperature and concentrateddown. EtOAc was added and washed with sat. NaHCO₃ aqueous (2×) and sat.NaCl aqueous (1×). The organic layer was concentrated down after dryingover sodium sulfate and subject to silica gel chromatography with aneluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCOcolumn (12 g silica gel). The fractions containing product were combinedand the solvent was removed under reduced pressure to provide(1R,3S,4S)-tert-butyl3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(110 mg, 88%). MS (ESI) m/z 734 [M+H]⁺.

To (1R,3S,4S)-tert-butyl3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(48 mg, 0.066 mmol) in dichloromethane (0.8 mL) was added 4M HCl indioxane (0.8 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 2 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (35 mg 0.048 mmol) in DMF (0.5 mL) was added(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(12.5 mg, 0.058 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (12 mg, 0.062 mmol) and hydroxybenzotriazole hydrate(HOBt), (8.4 mg, 0.062 mmol). The mixture was cooled down in an ice bathto 0° C. and N-methylmorpholine (NMM)(0.212 mmol) was added from asyringe to the mixture. The reaction content was stirred for 4 hours atroom temperature. The resulting mixture was then directly purified onreverse phase prep. HPLC to afford title compound as white solid (28 mg,70%). MS (ESI) m/z 833 [M+H]⁺.

Example JN

(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester

To (1R,3S,4S)-tert-butyl3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(48 mg, 0.066 mmol) in dichloromethane (0.8 mL) was added 4M HCl indioxane (0.8 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 2 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (35 mg 0.048 mmol) in DMF (0.5 mL) was added(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (11 mg, 0.058mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12mg, 0.062 mmol) and hydroxybenzotriazole hydrate (HOBt), (8.4 mg, 0.062mmol). The mixture was cooled down in an ice bath to 0° C. andN-methylmorpholine (NMM)(0.212 mmol) was added from a syringe to themixture. The reaction content was stirred for 4 hours at roomtemperature. The resulting mixture was then directly purified on reversephase prep. HPLC to afford title compound as white solid (29 mg, 75%).MS (ESI) m/z 807 [M+H]⁺.

Example JO

(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.11]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester

To (1R,3S,4S)-tert-butyl3-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(115 mg, 0.17 mmol) in dichloromethane (1 mL) was added 4M HCl indioxane (0.8 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 4 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (80 mg, 0.13 mmol) in DMF (1.3 mL) was added(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (58 mg, 0.3mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (64mg, 0.325 mmol) and hydroxybenzotriazole hydrate (HOBt), (44 mg, 0.325mmol). The mixture was cooled down in an ice bath to 0° C. andN-methylmorpholine (NMM)(0.868 mmol) was added from a syringe to themixture. The reaction content was stirred for 16 hours at roomtemperature. The resulting mixture was then directly purified on reversephase prep. HPLC to afford title compound as white solid (90 mg, 85%).MS (ESI) m/z 823 [M+H]⁺.

Example JP

(S)-2-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

To (1R,3S,4S)-tert-butyl3-(5-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(115 mg, 0.17 mmol) in dichloromethane (1 mL) was added 4M HCl indioxane (0.8 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 4 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (25 mg, 0.04 mmol) in DMF (0.4 mL) was added(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (22mg, 0.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (19 mg, 0.1 mmol) and hydroxybenzotriazole hydrate (HOBt),(14 mg, 0.1 mmol). The mixture was cooled down in an ice bath to 0° C.and N-methylmorpholine (NMM)(0.262 mmol) was added from a syringe to themixture. The reaction content was stirred for 16 hours at roomtemperature. The resulting mixture was then directly purified on reversephase prep. HPLC to afford title compound as white solid (28 mg, 80%).MS (ESI) m/z 876 [M+H]⁺.

Example JQ

(1R,3 S,4S)-tert-butyl3-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To (1R,3 S,4S)-tert-butyl3-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(88 mg, 0.14 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (53 mg, 0.168mmol), Pd(PPh₃)₄ (8 mg, 0.007 mmol). DME (1.4 mL) was added and followedby 0.56 mL 1M NaHCO₃ aqueous solution. The reaction was purged with Arand heated to 120° C. at microwave synthesizer for 0.5 hour. Thereaction was cooled to room temperature and concentrated down. EtOAc wasadded and washed with sat. NaHCO₃ aqueous (2×) and sat. NaCl aqueous(1×). The organic layer was concentrated down after drying over sodiumsulfate and subject to silica gel chromatography with an eluent of ethylacetate and hexane at a gradient of 40-100% with an ISCO column (12 gsilica gel). The fractions containing product were combined and thesolvent was removed under reduced pressure to provide title compound (90mg, 86%). MS (ESI) m/z 727 [M+H]⁺.

Example JR

(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(6-(7-(2-((S)-1-((2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester

To 1R,3S,4S)-tert-butyl3-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(90 mg, 0.12 mmol) in dichloromethane (1.2 mL) was added 4M HCl indioxane (1 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 2 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (30 mg 0.046 mmol) in DMF (0.5 mL) was added(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (20 mg, 0.105mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (22mg, 0.12 mmol) and hydroxybenzotriazole hydrate (HOBt), (16 mg, 0.12mmol). The mixture was cooled down in an ice bath to 0° C. andN-methylmorpholine (NMM)(0.223 mmol) was added from a syringe to themixture. The reaction content was stirred for 4 hours at roomtemperature. The resulting mixture was then directly purified on reversephase prep. HPLC to afford title compound as white solid (28 mg, 70%).MS (ESI) m/z 874 [M+H]⁺.

Example JS

(S)-2-((1R,3S,4S)-3-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

To (1R,3S,4S)-tert-butyl3-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(90 mg, 0.12 mmol) in dichloromethane (1.2 mL) was added 4M HCl indioxane (1 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 2 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (25 mg 0.038 mmol) in DMF (0.4 mL) was added(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (19mg, 0.09 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (18 mg, 0.095 mmol) and hydroxybenzotriazole hydrate(HOBt), (13 mg, 0.095 mmol). The mixture was cooled down in an ice bathto 0° C. and N-methylmorpholine (NMM)(0.252 mmol) was added from asyringe to the mixture. The reaction content was stirred for 4 hours atroom temperature. The resulting mixture was then directly purified onreverse phase prep. HPLC to afford title compound as white solid (24 mg,68%). MS (ESI) m/z 926 [M+H]⁺.

Example JT

(R)-2-((1R,3S,4S)-3-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

To (1R,3S,4S)-tert-butyl3-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(190 mg, 0.3 mmol), methyl(S)-2-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate(149 mg, 0.36 mmol), Pd(PPh₃)₄ (17 mg, 0.015 mmol). DME (3 mL) was addedand followed by 1.2 mL 1M NaHCO₃ aqueous solution. The reaction waspurged with Ar and heated to 120° C. at microwave synthesizer for 0.5hour. The reaction was cooled to room temperature and concentrated down.EtOAc was added and washed with sat. NaHCO₃ aqueous (2×) and sat. NaClaqueous (1×). The organic layer was concentrated down after drying oversodium sulfate and subject to silica gel chromatography with an eluentof ethyl acetate and hexane at a gradient of 40-100% with an ISCO column(12 g silica gel). The fractions containing product were combined andthe solvent was removed under reduced pressure to provide product (223mg, 88%). MS (ESI) m/z 826 [M+H]⁺.

(1R,3 S,4S)-tert-butyl3-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(100 mg, 0.12 mmol) in dichloromethane (1.2 mL) was added 4M HCl indioxane (1 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 2 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (20 mg 0.024 mmol) in DMF (0.25 mL) was addedmethoxycarbonylamino)-2-phenylacetic acid (5.4 mg, 0.026 mmol), COMU (13mg, 0.03 mmol). The mixture was cooled down in an ice bath to 0° C. andDIEA (0.072 mmol) was added from a syringe to the mixture. The reactioncontent was stirred for 1 hour at room temperature. The resultingmixture was then directly purified on reverse phase prep. HPLC to affordtitle compound as white solid (14 mg, 65%). MS (ESI) m/z 918 [M+H]⁺.

Example JU

(2S,3R)-3-methoxy-1-((S)-2-(5-(2-(2-((S)-1-((2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-8-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamicacid methyl mester

To (2S,2′S)-tert-butyl2,2′-(5,5′-(6H-dibenzo[c,h]chromene-2,8-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(90 mg, 0.128 mmol) in dichloromethane (1.2 mL) was added 4M HCl indioxane (1 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 2 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (80 mg 0.125 mmol) in DMF (1.2 mL) was added(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (62 mg, 0.33mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (62mg, 0.33 mmol) and hydroxybenzotriazole hydrate (HOBt), (44 mg, 0.33mmol). The mixture was cooled down in an ice bath to 0° C. andN-methylmorpholine (NMM)(0.828 mmol) was added from a syringe to themixture. The reaction content was stirred for 4 hours at roomtemperature. The resulting mixture was then directly purified on reversephase prep. HPLC to afford title compound as white solid (74 mg, 70%).MS (ESI) m/z 849 [M+H]⁺.

Example JV

(S)1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-(benzyloxycarbonylamino)-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazole-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

To (S)-tert-butyl2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(73 mg, 0.1 mmol) in dichloromethane (1.2 mL) was added 4M HCl indioxane (1 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 2 hours. After concentrated in vacuo to afford HCl salts.

This HCl salts (68 mg 0.1 mmol) in DMF (1 mL) was added(S)-2-(benzyloxycarbonylamino)-2-(tetrahydro-2H-thiopyran-4-yl)aceticacid (40 mg, 0.13 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (25 mg, 0.13 mmol) and hydroxybenzotriazole hydrate(HOBt), (18 mg, 0.13 mmol). The mixture was cooled down in an ice bathL, to 0° C. and N-methylmorpholine (NMM)(0.444 mmol) was added from asyringe to the mixture. The reaction content was stirred for 4 hours atroom temperature. The resulting mixture was then directly purified onreverse phase prep. HPLC to afford title compound as white solid (77 mg,90%). MS (ESI) m/z 924 [M+H]⁺.

Example JW

Methyl(S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-amino-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

To(S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-(benzyloxycarbonylamino)-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester (46 mg, 0.05 mmol) in ACN (0.4 mL) was add 33% HBr inHOAc (0.1 mL) and reaction mixture was cooled to 0° C. and then stirredfor 2 hours. After concentrated to afford title compound as white solid(33 mg, 85%). MS (ESI) m/z 790 [M+H]⁺.

Example JX

(S)-2-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-thiopyran-4-yl)ethylcarbamicacid methyl ester

To methyl(S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-amino-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(30 mg, 0.06 mmol) in water (0.3 mL) was add Na₂CO₃ (13 L, 0.09 mmol).The reaction mixture was cooled to 0° C. and methyl chloroformate(0.12mmol) was added and then stirred for 2 hours. The resulting mixture wasthen directly purified on reverse phase prep. HPLC to afford titlecompound as white solid (20 mg, 65%). MS (ESI) m/z 848 [M+H]⁺.

Example JY

(S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-(benzyloxycarbonylamino)-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of(S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-(benzyloxycarbonylamino)-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 924 [M+H]⁺.

Example JZ

(2S,3R)-3-methoxy-1-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 806 [M+H]⁺.

Example KA

(2S,3S)-3-methoxy-1-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 806 [M+H]⁺.

Example KB

(2S,3R)-3-tert-butoxy-1-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 848 [M+H]⁺

Example KC

2-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(pyrazin-2-yl)ethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 826[M+H]⁺.

Example KD

Methyl(S)-3-methyl-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-(nicotinamido)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of(R)-2-((1R,3S,4S)-3-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester, MS (ESI) m/z 871 [M+H]⁺.

Example KE

2-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(pyridin-3-yl)ethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 825[M+H]⁺.

Example KF

Methyl(2S)-1-((2S)-2-(5-(6-(4-(2-((2S)-1-(2-(benzo[d][1,3]dioxol-5-yl)-2-(dimethylamino)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 838[M+H]⁺.

Example KG

2-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)ethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 892[M+H]⁺.

Example KH

1-(Benzo[d][1,3]dioxol-5-yl)-2-((S)-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxoethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 868[M+H]⁺.

Example KI

Methyl(2S)-1-((2S)-2-(5-(6-(4-(2-((2S)-1-(2-(diethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 822[M+H]⁺.

Example KJ

Methyl(2S)-1-((2S)-2-(5-(6-(4-(2-((2S)-1-(2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-tH-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 794[M+H]⁺.

Example KK

Methyl(2S)-3-methyl-1-((2S)-2-(5-(6-(4-(2-((2S)-1-(2-morpholino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 836[M+H]⁺.

Example KL

Methyl(2S)-1-((2S)-2-(5-(4-(6-(2-((2S)-1-(2-(diethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 822[M+H]⁺.

Example KM

Methyl(2S)-3-methyl-1-oxo-1-((2S)-2-(5-(4-(6-(2-((2S)-1-(2-phenyl-2-(pyrrolidin-1-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 820[M+H]⁺.

Example KN

Methyl(2S)-3-methyl-1-((2S)-2-(5-(4-(6-(2-((2S)-1-(2-morpholino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 836[M+H]⁺.

Example KO

Methyl(2S)-3-methyl-1-((1R,3S,4S)-3-(5-(4-(6-(2-((6S)-5-(2-morpholino-2-phenylacetyl)-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of(2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 888[M+H]⁺.

Example KP

Methyl (1S)-2-((2S)-2-(5-(4-(6-(2-((2S)-1-(2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1T-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 836[M+H]⁺.

Example KQ

(R)-2-((S)-2-(5-(4-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of(R)-2-((1R,3S,4S)-3-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester, MS (ESI) m/z 898[M+H]⁺.

Example KR

Methyl(2S)-1-((2S)-2-(5-(7-(4-(2-((2S)-1-(2-(diethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3 S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 896[M+H]⁺.

Example KS

(S)-2-((S)-2-(5-(4-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 906[M+H]⁺.

Example KT

(S)-2-((S)-2-(5-(4-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 948[M+H]⁺.

Example KU

(R)-2-((S)-2-(5-(4-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of(R)-2-((1R,3S,4S)-3-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamicacid methyl ester, MS (ESI) m/z 940[M+H]⁺.

Example KV

(S)-2-((S)-2-(5-(4-(9,9-difluoro-7-(2-((S)-5-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-azaspiro[2.4]heptan-6-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 932[M+H]⁺.

Example KW

(2S,3R)-1-((S)-2-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamicacid methyl ester

Title compound was synthesized using methods analogous to thepreparation of (2S,3R)-3-methoxy-1-((1R,3S,4S)-3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-oxobutan-2-ylcarbamicacid methyl ester, MS (ESI) m/z 854[M+H]⁺.

Example KX

2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester

This compound was prepared as described in Example ES.

[2-Ethyl-1-(2-{5-[6-(4-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-butyl]-carbamicacid methyl ester

This compound was prepared according to the procedure used to prepare{2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamicacid methyl ester (Example ES) using3-Ethyl-2-methoxycarbonylamino-pentanoic acid (0.032g, 0.156 mmol) togive the title compound (0.023, 21% yield) as a white solid. LCMS-ESI⁺:calc'd for C₄₉H₅₄N₈O₆: 850.42 (M⁺). Found: 851.5 (M+H⁺).

Example KY

(S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-tert-butyl2-(6-bromo-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate (4.06 g,11.1 mmol), bis(pinacolato)diboron (4.22 g, 16.6 mmol), PdCl₂(dppf) (406mg, 0.55 mmol) and potassium acetate (3.3 g, 33.2 mmol) in dioxane (33mL) was degassed with a stream of argon. After twenty minutes, thismixture was heated to 90° C. After 3 hours, the mixture was cooled toroom temperature. The reaction was diluted with ethyl acetate, washedwith saturated aqueous NaHCO₃ solution, dried (Na₂SO₄) and concentrated.The crude material was purified by flash column chromatography to yield(S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.49 g, 33%).

(S)-tert-butyl2-(6-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate

A mixture of ((S)-tert-butyl2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.49 g, 3.6 mmol), 2,7-dibromo-9,10-dihydrophenanthrene (6.09 g, 18.0mmol), 2M aqueous potassium carbonate solution (9 mL, 18.0 mmol),tetrakis(triphenylphosphine)palladium(0) (209 mg, 0.18 mmol) anddimethoxyethane (36 mL) was degassed with a stream of argon for twentyminutes. The reaction was heated to 85° C. After 16 hours, the reactionwas cooled to room temperature and diluted with ethyl acetate. Theorganic phase was washed with saturated aqueous NaHCO₃ solution andbrine, dried (Na₂SO₄) and concentrated. The crude material was purifiedby flash column chromatography to yield (S)-tert-butyl2-(6-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate(1.16 g, 59%).

Methyl(S)-1-((S)-2-(6-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of (S)-tert-butyl2-(6-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate(582 mg, 1.1 mmol), 4M HCl solution in dioxanes (5 mL, 20 mmol) andmethanol (3 mL) was stirred at room temperature for twenty minutes. Thereaction was concentrated, suspended in dichloromethane, and thoroughlyconcentrated. This crude amine was dissolved in dimethylformamide (5mL). To this solution were added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (281 mg, 1.6 mmol),HATU (691 mg, 1.8 mmol) and diisopropylethylamine (0.65 mL, 3.7 mmol).The reaction was stirred at room temperature for fifteen minutes, andthen diluted ethyl acetate. The organic layer was washed with saturatedaqueous NaHCO₃ solution and brine, dried (Na₂SO₄) and concentrated. Thecrude material was purified by flash column chromatography to yieldMethyl(S)-1-((S)-2-(6-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(376 mg, 58%).

(S)-tert-butyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of methylS)-1-((S)-2-(6-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(376 mg, 0.62 mmol), bis(pinacolato)diboron (167 mg, 0.66 mmol),PdCl₂(dppf) (23 mg, 0.03 mmol) and potassium acetate (184 mg, 1.9 mmol)in dioxane (3 mL) was degassed with a stream of argon for twentyminutes. The reaction was heated to 100° C. After 1 hour, the mixturewas cooled to room temperature. To the reaction was added (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (296 mg, 0.94mmol), 2M aqueous potassium phosphate solution (0.94 mL, 1.9 mmol) anddimethoxyethane (4 mL). The reaction was degassed with a stream of argonfor twenty minutes. The reaction was heated in a microwave to 130° C.for twenty minutes. After cooling, more PdCl₂(dppf) (23 mg, 0.03 mmol),2M aqueous potassium phosphate solution (0.47 mL, 0.94 mmol), and(S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (98mg, 0.31 mmol) were added and the reaction was heated in a microwave to120° C. for 140 minutes. The reaction was removed from the microwave andheated at 110° C. overnight. After 14 hours, the reaction was dilutedwith ethyl acetate, and the organic phase was washed with saturatedaqueous NaHCO₃ solution and brine, dried (Na₂SO₄) and concentrated. Thecrude material was purified by flash column chromatography to yield(S)-tert-butyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(174 mg, 37%).

Methyl(R)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

A solution of (S)-tert-butyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(174 mg, 0.23 mol), methanol (0.5 mL), and 4M HCl in dioxane (2 mL, 8mmol) was stirred at room temperature. The reaction was thoroughlyconcentrated after ten minutes. The resulting residue was dissolved in a4:1 dichloromethane:dimethylformamide solution (2.3 mL). One half ofthis solution was removed and used in the subsequent reaction. To thissolution (˜1.15 mL) was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (24 mg, 0.13 mmol) andCOMU (49 mg, 0.11 mmol) and the reaction was cooled to 0° C.Diisopropylethylamine (0.080 mL, 0.46 mmol) was added and the reactionwas stirred at 0° C. for twenty minutes. The reaction was quenched bythe addition of formic acid (0.05 mL) and thoroughly concentrated. Theresulting residue was purified by preparative reverse phase HPLC(Gemini, 10 to 60% ACN/H₂O+0.1% HCO₂H), followed by a second preparativereverse phase HPLC (Gemini, 10 to 60% ACN/H₂O+0.1% TFA) to yield methyl(R)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(51 mg, ˜52%). LCMS-ESI⁺: calculated for C₄₉H₅₂N₈O₆: 848.50; observed[M+1]⁺: 849.59.

Example KZ

methyl(2S)-1-((2S)-2-(6-(7-(2-((2S)-1-(2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(2S)-1-((2S)-2-(6-(7-(2-((2S)-1-(2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:This compound was made in an analogous manner to methyl(R)-2-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate,substituting (R)-2-(dimethylamino)-2-phenylacetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amidecoupling. LCMS-ESI⁺: calculated for C₄₉H₅₄N₈O₄: 819.00. observed [M+1]⁺:819.80.

Example LA

Methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 3.2 mmol),4M HCl solution in dioxanes (3.95 mL, 15.8 mmol) and methanol (4 mL) wasstirred at room temperature for thirty minutes. The reaction wasconcentrated, suspended in dichloromethane, and thoroughly concentrated.This crude amine was dissolved in dimethylformamide (6.4 mL). To thissolution were added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(582 mg, 3.3 mmol), HATU (1.3 g, 3.3 mmol) and diisopropylethylamine(1.9 mL, 11.1 mmol). The reaction was stirred at room temperature fortwenty minutes, and then diluted with ethyl acetate. The organic layerwas washed with water and brine, dried (Na₂SO₄) and concentrated. Thecrude material was purified by flash column chromatography to yieldmethyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(985 mg, 83%).

Example LB

(S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-tert-butyl2-(6-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate(582 mg, 1.1 mmol), bis(pinacolato)diboron (407 mg, 1.6 mmol),PdCl₂(dppf) (39 mg, 0.05 mmol) and potassium acetate (315 mg, 3.2 mmol)in dioxane (5 mL) was degassed with a stream of argon for twentyminutes. The reaction was heated to 100° C. After forty minutes, themixture was cooled to room temperature and diluted with ethyl acetate.The organic phase was washed with water and brine, dried (Na₂SO₄) andconcentrated. The resulting residue was purified by flash columnchromatography to yield (S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(590 mg, 93%).

(S)-tert-butyl2-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-tert-butyl2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(590 mg, 1.0 mmol), methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(492 mg, 1.3 mmol), PdCl₂(dppf) (37 mg, 0.05 mmol), 2M aqueous potassiumphosphate solution (1.5 mL, 3.0 mmol), and dimethoxyethane (5 mL) wasdegassed with a stream of argon for twenty minutes. The reaction washeated to 90° C. After one hour, the reaction was cooled to roomtemperature and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05mmol) was added. The reaction was heated to 90° C. After three hours,the reaction was cooled to room temperature and more PdCl₂(dppf) (37 mg,0.05 mmol) was added. The reaction was heated to 80° C. After 16 hours,the reaction was cooled to room temperature and diluted with ethylacetate. The organic phase was washed with water and brine, dried(Na₂SO₄) and concentrated. The resulting residue was purified by flashcolumn chromatography to yield (S)-tert-butyl2-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(30 mg, 4%).

Methyl(S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of (S)-tert-butyl2-(6-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(30 mg, 0.04 mol), methanol (0.5 mL), and 4M HCl in dioxane (1 mL, 4mmol) was stirred at room temperature. The reaction was thoroughlyconcentrated after twenty minutes. The resulting residue was dissolvedin a 4:1 dichloromethane:dimethylformamide solution (1.0 mL). One halfof this solution was removed and used in the subsequent reaction. Tothis solution (˜0.5 mL) was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (4.2 mg, 0.02 mmol) andCOMU (8.5 mg, 0.02 mmol) and the reaction was cooled to 0° C.Diisopropylethylamine (0.011 mL, 0.06 mmol) was added and the reactionwas stirred at 0° C. for twenty minutes. The reaction was quenched bythe addition of formic acid (0.05 mL) and thoroughly concentrated. Theresulting residue was purified by preparative reverse phase HPLC(Gemini, 10 to 60% ACN/H₂O+0.1% HCO₂H), followed by a second preparativereverse phase HPLC (Gemini, 10 to 60% ACN/H₂O+0.1% TFA) to yield methyl(S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(6 mg, 36%). LCMS-ESI⁺: calculated for C₄₉H₅₂N₈O₆: 848.99. observed[M+1]⁺: 850.2.

Example LC

methyl(2S)-1-((2S)-2-(5-(7-(2-((2S)-1-(2-(dimethylamino)-2-phenylacetyl)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(2S)-1-((2S)-2-(5-(7-(2-((2S)-1-(2-(dimethylamino)-2-phenylacetyl)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate:This compound was made in an analogous manner to methyl(S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (R)-2-(dimethylamino)-2-phenylacetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the final amidecoupling step. LCMS-ESI⁺: calculated for C₄₉H₅₄N₈O₄: 819.00. observed[M+1]⁺: 820.3.

Example LD

2,7-Dibromo-9,9-difluoro-9H-fluorene

2,7-Dibromo-fluoren-9-one (4.0 g, 11.8 mmol) was suspended in deoxofluor(12 mL) at room temperature and EtOH (4 drops) was added. The stirredsuspension was heated at T=90° C. for 24 hours (CAUTION: Use ofdeoxofluor at elevated temperatures, as described above, is stronglydiscouraged as rapid and violent exotherms may occur). The reaction wascooled to room temperature and poured onto ice containing sodiumbicarbonate. A solid formed and was collected via filtration. The crudematerial was taken into EtOAc and was washed with aqueous HCl (1M) andbrine. The solution was dried over sodium sulfate. Filtration andevaporation of solvents gave crude product, which was purified by silicagel chromatography (eluent: EtOAc/hexanes) to yield the product2,7-Dibromo-9,9-difluoro-9H-fluorene (3.2 g). ¹⁹F-NMR: 282 MHz,(dmso-d₆) δ: −111.6 ppm.

Before using the material in the next step, it was exposed as a solutionin EtOAc to charcoal.

5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester6-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester

2,7-Dibromo-9,9-difluoro-9H-fluorene (372 mg, 1.04 mmol), Pd(PPh₃)₄(30.0 mg, 0.026 mmol), PdCl₂(PPh₃)₂ (18.2 mg, 0.026 mmol), As(PPh₃)₃(5.0 mg) were dissolved in dioxane (10 mL) under an argon atmosphere.Ethoxyvinyl-tributyl tin (376.4 mg, 1.04 mmol) was added. The mixturewas heated for 140 minutes at 85° C. (oil bath). The reaction was cooledto room temperature. N-bromo succinimide (177 mg, 1.0 mmol) was addedfollowed by water (2 mL). The reaction was stirred at room temperaturefor 3 hours, after which the majority of the dioxane was removed invacuo. The crude reaction mixture was diluted with EtOAc and was washedwith water. All volatiles were removed in vacuo. Toluene was added andall volatiles were removed in vacuo for a second time. The crudematerial was dissolved in DMF/MeCN (2 mL, 1:1) at room temperature. Asolution of N-Cbz-4-cyclopropyl (L) Proline (0.84 mmol) and DIEA (268mg, 2.08 mmol) in MeCN (2 mL) was added and stirring at room temperaturewas continued. After 14 hours, most of the MeCN was removed in vacuo andthe crude reaction mixture was diluted with EtOAc. The mixture waswashed with aqueous HCl (1M), aqueous LiCl solution (5%), brine, and wasdried over sodium sulfate. Filtration and evaporation of solvents gavethe crude reaction product, which was purified via silica gelchromatography (eluent: EtOAc/hexanes) to yield the product5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester6-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester (176 mg).LCMS-ESI⁺: calc'd for C₃₀H₂₄BrF₂NO₅: 596.4 (M⁺). Found: 595.2/597.2(M+H⁺).

6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester

5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester6-[2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxo-ethyl]ester (172 mg,0.293 mmol) was dissolved in m-xylenes (6.0 mL). Ammonium acetate (226mg, 2.93 mmol) was added and the reaction was stirred at 140° C. for 60minutes under microwave conditions. The reaction was cooled to roomtemperature and all volatiles were removed in vacuo. The crude materialwas purified via silica gel chromatography (eluent: EtOAc/hexanes) toyield the product6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester (80.3 mg). LCMS-ESI⁺: calc'd for C₃₀H₂₄BrF₂N₃O₂: 576.4(M⁺). Found: 575.2/577.2 (M+H⁺).

(1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylicacid benzyl ester (800 mg, 1.38 mmol) was dissolved in DCM (15 mL) andHBr in AcOH (37%, 2 mL) was added and stirring at room temperature wascontinued. After 180 minutes, the suspension was diluted with hexanesand the solid was collected via filtration and was washed with hexanesand subjected to vacuum. The crude material was used in the next stepwithout further purification. The crude material was dissolved in DMF(4.0 mL) and DIEA (356 mg, 2.76 mmol) was added. A solution of2-(L)-Methoxycarbonylamino-3-methyl-butyric acid (242 mg, 1.38 mmol),HATU (524 mg, 1.38 mmol) and DIEA (178 mg, 1.38 mmol) in DMF (1 mL) wasadded. The reaction was stirred at room temperature. After 50 minutes,the reaction was diluted with EtOAc and was washed with aqueousbicarbonate solution, aqueous LiCl solution (5%), brine, and was driedover sodium sulfate. Filtration and removal of solvents in vacuo gavethe crude material, which was purified by silica gel chromatography(eluent: EtOAc/hexanes) to yield the slightly impure product(1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (878 mg). LCMS-ESI⁺: calc'd for C₂₉H₂₉BrF₂N₄O₃: 599.5(M⁺). Found: 598.5/600.5 (M+H⁺).

3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

(1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (840 mg, 1.4 mmol),3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (615 mg, 1.4 mmol), Pd(PPh₃)₄ (161 mg, 0.14 mmol),K₂CO₃ (579 mg, 4.2 mmol), were dissolved in DME (15 mL)/water (3 mL)under an argon atmosphere. The mixture was heated for 120 minutes at85-90° C. (oil bath). After 120 minutes additional boronate ester (61mg, 0.14 mmol) was added and heating was continued. After 3 hours, thereaction was cooled to room temperature. Most of the DME was removed invacuo and the crude reaction mixture was diluted with EtOAc. The mixturewas washed with brine and was dried over sodium sulfate. Filtration andevaporation of solvents gave the crude reaction product, which waspurified via silica gel chromatography (eluent: EtOAc/hexanes) to yieldthe product3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (878 mg). LCMS-ESI⁺: calc'd for C₄₇H₅₁F₂N₇O₅:831.9 (M⁺). Found: 832.7 (M+H⁺).

Methyl(S)-1-((S)-6-(5-(7-(2-((1R,3S,4S)-2-((R)-2-methoxycarbonylamino-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (28 mg, 0.03 mmol), methanol (0.5 mL), and 4M HClin dioxane (0.5 mL, 2 mmol) was stirred at room temperature. Thereaction was thoroughly concentrated after twenty minutes. The resultingresidue was dissolved in a 4:1 dichloromethane:dimethylformamidesolution (0.5 mL). To this solution was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (7.9 mg, 0.04 mmol) andCOMU (16 mg, 0.04 mmol) and the reaction was cooled to 0° C.Diisopropylethylamine (0.024 mL, 0.14 mmol) was added and the reactionwas stirred at 0° C. for ten minutes. The reaction was quenched by theaddition of formic acid (0.05 mL) and thoroughly concentrated. Theresulting residue was purified by preparative reverse phase HPLC(Gemini, 10 to 60% ACN/H₂O+0.1% TFA) to yield methyl(S)-1-((S)-6-(5-(7-(2-((1R,3S,4S)-2-((R)-2-methoxycarbonylamino-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate(10 mg, 36%). LCMS-ESI⁺: calc'd for C₅₂H₅₂F₂N₈O₆: 923.02 (M⁺). Found:924.5 (M+H⁺).

Example LE

(S)-2-(2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxoethyl) 1-tert-butylpyrrolidine-1,2-dicarboxylate

A mixture of 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone(2 g, 5.6 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid (1.32 g, 6.1 mmol), potassium carbonate (1.55 g, 11.1 mmol) andpotassium iodide (930 mg, 5.6 mmol) in acetone was heated to 60° C.After forty minutes, the reaction was cooled to room temperature andconcentrated. The residue was dissolved in a mixture of ethyl acetateand water. The aqueous phase was extracted twice with ethyl acetate. Thecombined organic layers were washed with saturated aqueous NH₄Clsolution and brine, dried (Na₂SO₄) and concentrated. The crude materialwas purified by flash column chromatography to yield(S)-2-(2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxoethyl) 1-tert-butylpyrrolidine-1,2-dicarboxylate (2.65 g, 88%).

(S)-tert-butyl2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (S)-2-(2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (2.65 g, 4.9 mmol), ammoniumacetate (3.8g, 49 mmol) and toluene was vigorously refluxed. After 4.5hours, the reaction was cooled to room temperature and diluted withethyl acetate. The organic layer was washed with saturated aqueousNaHCO₃ solution and brine, dried (Na₂SO₄) and concentrated. Theresulting crude residue was purified by flash column chromatography toyield (S)-tert-butyl2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(2.27g, 89%).

Methyl(S)-1-((S)-2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of (S)-tert-butyl2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.09 g, 2.1 mmol), methanol (10 mL), and 4M HCl in dioxane (10 mL, 40mmol) was stirred at room temperature. The reaction was thoroughlyconcentrated after one hour. The resulting residue was dissolved indimethylformamide (10.6 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (390 mg, 2.2 mmol)and HATU (847 mg, 2.2 mmol). Diisopropylethylamine (1.3 mL, 7.5 mmol)was added and the reaction was stirred at room temperature. After thirtyminutes, the reaction was diluted with ethyl acetate. The organic phasewas washed with water and brine, dried (Na₂SO₄) and concentrated. Thecrude material was purified by flash column chromatography to yieldmethyl(S)-1-((S)-2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(712 mg, 59%).

(1R,3S,4S)-tert-butyl3-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

A mixture of methyl(S)-1-((S)-2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(192 mg, 0.33 mmol), (1R,3S,4S)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(177 mg, 0.40 mmol), 1M aqueous sodium bicarbonate solution (1.27 mL,1.27 mmol), triphenylphosphine (9 mg, 0.03 mmol), palladium(II) acetate(4 mg, 0.02 mmol) and dimethoxyethane (3.5 mL) was degassed with astream of argon for twenty minutes. The reaction was heated to 95° C.After four hours, the reaction was cooled to room temperature anddiluted with ethyl acetate. The organic phase was washed with saturatedaqueous NaHCO₃ solution and brine, dried (Na₂SO₄) and concentrated. Thecrude material was purified by flash column chromatography to yield(1R,3S,4S)-tert-butyl3-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(204 mg, 76%).

Methyl(S)-1-((S)-2-(5-(7-(2-((1R,3S,4S)-2-((R)-2-methoxycarbonylamino-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of (1R,3S,4S)-tert-butyl3-(6-(9,9-difluoro-7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(204 mg, 0.25 mmol), methanol (2 mL), and 4M HCl in dioxane (2 mL, 4mmol) was stirred at room temperature. The reaction was thoroughlyconcentrated after thirty minutes. The resulting residue was dissolvedin a 4:1 dichloromethane:dimethylformamide solution (2.4 mL). Half ofthis solution was removed and used in the next reaction. To thissolution (˜1.2 mL) was added (R)-2-(methoxycarbonylamino)-2-phenylaceticacid (24 mg, 0.12 mmol) and COMU (50 mg, 0.12 mmol) and the reaction wascooled to 0° C. Diisopropylethylamine (0.060 mL, 0.35 mmol) was addedand the reaction was stirred at 0° C. for twenty minutes. The reactionwas quenched by the addition of formic acid (0.05 mL) and thoroughlyconcentrated. The resulting residue was purified by preparative reversephase HPLC (Gemini, 10 to 60% ACN/H₂O+0.1% TFA) to yield methyl(S)-1-((S)-2-(5-(7-(2-((1R,3S,4S)-2-((R)-2-methoxycarbonylamino-2-phenylacetyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(61 mg, 54%). LCMS-ESI⁺: calculated for C₅₀H₅₀F₂N₈O₆: 897.0. observed[M+1]⁺: 898.1.

Example LF

Methyl(S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate

A solution of (1R,3S,4S)-tert-butyl3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(1.0 g, 2.3 mmol), methanol (10 mL), and 4M HCl in dioxane (11 mL, 44mmol) was stirred at room temperature. The reaction was thoroughlyconcentrated after one hour. The resulting residue was dissolved indimethylformamide (11.4 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (419 mg, 2.4 mmol)and HATU (909 mg, 2.4 mmol). Diisopropylethylamine (1.4 mL, 8.1 mmol)was added and the reaction was stirred at room temperature. After thirtyminutes, the reaction was diluted with ethyl acetate. The organic phasewas washed with water and brine, dried (Na₂SO₄) and concentrated. Thecrude material was purified by flash column chromatography to yieldmethyl(S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate(1.08 g, 95%).

(S)-tert-butyl2-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of methyl(S)-3-methyl-1-oxo-1-((1R,3S,4S)-3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate(122 mg, 0.25 mmol), (S)-tert-butyl2-(5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(127 mg, 0.25 mmol), 1M aqueous sodium bicarbonate solution (0.93 mL,0.93 mmol), triphenylphosphine (13 mg, 0.05 mmol), palladium(II) acetate(5.5 mg, 0.02 mmol) and dimethoxyethane (2.5 mL) was degassed with astream of argon for twenty minutes. The reaction was heated to 95° C.After four hours, the reaction was cooled to room temperature anddiluted with ethyl acetate. The organic phase was washed with saturatedaqueous NaHCO₃ solution and brine, dried (Na₂SO₄) and concentrated. Thecrude material was purified by flash column chromatography to yield(S)-tert-butyl2-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(106 mg, 54%).

Methyl(R)-2-((S)-2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

A solution of (S)-tert-butyl2-(5-(9,9-difluoro-7-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(106 mg, 0.13 mmol), methanol (1.5 mL), and 4M HCl in dioxane (1.5 mL, 6mmol) was stirred at room temperature. The reaction was thoroughlyconcentrated after thirty minutes. The resulting residue was dissolvedin a 4:1 dichloromethane:dimethylformamide solution (1.3 mL). To thissolution was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (28mg, 0.13 mmol) and COMU (56 mg, 0.13 mmol) and the reaction was cooledto 0° C. Diisopropylethylamine (0.092 mL, 0.53 mmol) was added and thereaction was stirred at 0° C. for twenty minutes. The reaction wasquenched by the addition of formic acid (0.05 mL) and thoroughlyconcentrated. The resulting residue was purified by preparative reversephase HPLC (Gemini, 10 to 60% ACN/H₂O+0.1% TFA) to yield methyl(R)-2-((S)-2-(5-(7-(2-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazol-6-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(28 mg, 24%). LCMS-ESI⁺: calculated for C₅₀H₅₀F₂N₈O₆: 897.0. observed[M+1]⁺: 898.1.

Example LG

2-(5-{6-[4-(2-{1-[2-Benzyloxycarbonyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester

This compound was prepared according to the procedure described inExample ER.

2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester

This compound was prepared according to the procedure used to make(1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (Example GG) using2-(5-{6-[4-(2-{1-[2-Benzyloxycarbonyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.502g, 0.708 mmol) and2-Methoxycarbonylamino-propionic acid (0.190g, 1.29 mmol) to give2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester (0.74g, >99% yield) as a white solid. LCMS-ESI⁺:calc'd for C₄₃H₄₃N₇O₅: 737.33 (M⁺). Found: 738.79 (M+H⁺).

[2-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamicacid methyl ester

To a solution of2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid benzyl ester (0.522 g, 0.708 mmol) in EtOH (7.1 mL) was addedPalladium on carbon (10%, 0.015 g, 0.150 mmol) and Potassium Carbonate(0.196 g, 0.1.416 mmol). The slurry was stirred at room temperatureunder an atmosphere of H2 for 72 h. The slurry was filtered throughcelite and washed with EtOH. The filtrate was concentrated to an oil andslurried in CH2Cl2 (3.23 mL). Methoxycarbonylamino-phenyl-acetic acid(0.101 g, 0.0.484 mmol) and Potassium Phosphate (0.205 g, 0.968 mmol)were added and the resulting solution was cooled to 0° C. (external,ice). COMU (0.172 g, 0.403 mmol) was added and the reaction was stirredat 0° C. for 2 h. The resulting solution was concentrated, diluted withDMF and filtered. Purification by preparative HPLC (Gemini, 15→40% MeCNin H₂O (0.1% formic acid)) and lyophilization provided[2-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamicacid methyl ester (0.174 g, 68%). LCMS-ESI⁺: calc'd for C₄₅H₄₆N₈O₆:794.35 (M⁺). Found: 795.89 (M+H⁺).

Example LH

A Mixture of (S)-tert-butyl2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene

A solution of (2S,2′S)-tert-butyl2,2′-(5,5′-(5,10-dihydrochromeno-[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))-dipyrrolidine-1-carboxylate(505 mg, 0.74 mmol), 4M hydrogen chloride in dioxane (1.85 mL, 7.4mmol), dioxane (10 mL) and methanol (2 mL) was stirred at roomtemperature. After 2.5 hours, the reaction was concentrated. Theresulting residue was suspended in toluene and thoroughly concentratedto yield a crude mixture containing (S)-tert-butyl2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateand2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromenein a molar ratio of approximately 1:1. This mixture was used in the nextstep without further purification.

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

The mixture of (S)-tert-butyl2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-H-imidazol-2-yl)pyrrolidine-1-carboxylateand2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromeneobtained in the previous step was dissolved in dimethylformamide (6 mL).To this solution was added (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (194 mg, 1.11 mmol), HATU (309 mg, 0.81 mmol), andN-methylmorpholine (0.24 mL, 2.2 mmol). The reaction was stirred at roomtemperature for thirty minutes, and then quenched by the addition offormic acid (0.05 mL). The reaction was concentrated and the resultingresidue was purified by preparative reverse phase HPLC (Gemini, 10 to45% ACN/H₂O+0.1% TFA) to yield methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(59 mg, 12%) as the tris-TFA salt. Also isolated from the reaction were(S)-tert-butyl2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(124 mg, 23%) and dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno-[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(50 mg, 8%).

Example LI

Methyl(S)-1-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of the tris-TFA salt of methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(59 mg) in methanol was filtered through an ion exchange column(Stratospheres™ PL-HCO₃MP SPE, Part #: PL3540-C603). The column wasrinsed with methanol and the filtrate was concentrated to yield methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(36 mg, 0.056 mmol) as the freebase. This material was dissolved indimethylformamide (2 mL). One half of this solution was used in the nextreaction. To this solution (1 mL, 0.028 mmol) was added(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(12.3 mg, 0.057 mmol), HATU (12.8 mg, 0.034 mmol) and N-methylmorpholine(0.009 mL, 0.08 mmol). The reaction was stirred at room temperature fortwenty minutes, and then quenched by the addition of formic acid (0.03mL) The reaction was concentrated and the resulting residue was purifiedby preparative reverse phase HPLC (Gemini, 10 to 45% ACN/H₂O+0.1% TFA)to yield methyl(S)-1-((S)-2-(5-(7-(2-((S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(20 mg, 85%). LCMS-ESI⁺: calculated for C₄₄H₅₂N₈O₉: 836.39; observed[M+1]⁺: 837.49.

Example LJ

Methyl(S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

A solution of the tris-TFA salt of methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(59 mg) in methanol was filtered through an ion exchange column(Stratospheres™ PL-HCO₃MP SPE, Part #: PL3540-C603). The column wasrinsed with methanol and the filtrate was concentrated to yield methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(36 mg, 0.056 mmol) as the freebase. This material was dissolved indimethylformamide (2 mL). One half of this solution was used in the nextreaction. To this solution (1 mL, 0.028 mmol) at 0° C. was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (11.7 mg, 0.056 mmol),COMU (13.2 mg, 0.031 mmol) and diisopropylethylamine (0.015 mL, 0.084mmol). The reaction was stirred at 0 OC for twenty minutes, and thenquenched by the addition of formic acid (0.03 mL) The reaction wasconcentrated and the resulting residue was purified by preparativereverse phase HPLC (Gemini, 10 to 45% ACN/H₂O+0.1% TFA) to yield methyl(S)-1-((S)-2-(5-(7-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(19 mg, 82%). LCMS-ESI⁺: calculated for C₄₅H₄₈N₈O₈: 828.91; observed[M+1]⁺: 829.75.

Example LK

Dimethyl(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate

A solution of (2S,2′S)-tert-butyl2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))-dipyrrolidine-1-carboxylate(190 mg, 0.28 mmol) and concentrated hydrogen chloride (1 mL) in ethanol(10 mL) was heated to 65° C. After thirty five minutes the reaction wasconcentrated. The residue was suspended in toluene and thoroughlyconcentrated. A portion of this deprotected amine (49 mg, 0.078 mmol)was dissolved in dimethylformamide (2 mL). To this solution at 0° C. wasadded (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (49 mg, 0.23mmol), COMU (73 mg, 0.17 mmol) and diisopropylethylamine (0.068 mL, 0.39mmol). After thirty minutes, the reaction was quenched by the additionof formic acid (0.03 mL). The reaction was concentrated and theresulting residue was purified by preparative reverse phase HPLC(Gemini, 10 to 50% ACN/H₂O+0.1% TFA). The HPLC fractions containingproduct were combined and concentrated to remove most of theacetonitrile. Saturated aqueous NaHCO₃ solution was added until theproduct-containing solution became basic. The aqueous phase wasextracted three times with ethyl acetate. The combined organic layerswere washed once with brine, dried (Na₂SO₄) and concentrated to yielddimethyl(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate(45.4 mg, 67%). LCMS-ESI⁺: calculated for C₄₈H₄₆N₈O₈: 862.93. observed[M+1]⁺: 863.73.

Example LL

A solution of 5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diylbis(trifluoromethanesulfonate) (5.06g, 10.09 mmol) and triethylamine(5.9 mL, 40 mmol) in DMF (100 mL) was degassed with argon for 15minutes, then 1,3-diphenylphosphinopropane (412 mg, 1 mmol) andpalladium acetate (224 mg, 1 mmol) were added under argon. The mixturewas heated at 80° C. overnight. The reaction mixture was concentrated byrotary evaporation and then dried further under high vacuum overnight toobtain intermediate2,7-bis(1-butoxyvinyl)-5,10-dihydrochromeno[5,4,3-cde]chromene as acrude brown solid. ¹H-NMR of this solid in DMSO-d₆ is consistent withdesired product and triethylammonium triflate.

Intermediate2,7-bis(1-butoxyvinyl)-5,10-dihydrochromeno[5,4,3-cde]chromene wastreated with THF (51 mL), water (17 mL), and then N-bromosuccinimide(3.74g, 21 mmol) and stirred at room temperature. The dark solutionbecomes an orange suspension within 15 minutes. After 1.5 hours, 200 mLof ethyl acetate was added and the mixture was filtered. The collectedsolid was washed with two 60 mL portions of water, three 60 ml portionsof ethyl acetate, and three 60 mL portions of diethyl ether. The solidwas air dried to give 3.15g (69.6% yield) as a yellow powder. ¹H NMR inDMSO-d₆ is consistent with product C, containing a small amount of anunknown impurity. Note: product C requires some heating to dissolve inDMSO.

To a mixture of1,1′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-bromoethanone)(2.7g, 5.5 mmol) and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid (2.61 g, 13.75 mmol) in 50 mL DMF was added triethylamine (2.4 mL,13.75 mmol). The reaction was stirred at room temperature overnight. Thecrude reaction mixture was diluted with 150 mL water and the resultingprecipitate was collected by vacuum filtration as a dark yellow solid,3.18 g, 4.41 mmol) (2S,2′S)-1-tert-butyl‘2,2-2,2’-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-oxoethane-2,1-diyl)dipyrrolidine-1,2-dicarboxylate

A mixture of (2S,2′S)-1-tert-butyl‘2,2-2,2’-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-oxoethane-2,1-diyl)dipyrrolidine-1,2-dicarboxylate(3.18g, 4.41 mmol), ammonium acetate (3.4g, 44.1 mmol) and toluene (40mL) was heated at reflux for 2 hours then cooled to room temperature anddiluted with ethyl acetate. This gave a precipitate which was collectedby vacuum filtration (1.89g). The filtrate was concentrated andchromatographed using 0-10% methanol in DCM for another 0.96g. Totalyield 2.85g of (2S,2′S)-tert-butyl2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate

(2S,2′S)-tert-butyl2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))dipyrrolidine-1-carboxylate(0.96g, 1.41 mmol) was treated with 20 mL 1.25N HCl in ethanol at 40° C.for 3 hours. Concentration followed by trituration with 100 mL diethylether gave2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromenetetrahydrochloride

(700.7 mg, 1.19 mmol) as a dark orange solid.

To a solution of (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid(90 mg),2,7-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromenetetrahydrochloride (118 mg), and N,N-diisopropylethylamine (216 μL) in 2mL DMF was added(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (172 mg) in an ice bath. Additional(R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (60 mg, 0.238 mmol)and(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate were added in small portions until the reaction wascomplete by LCMS. The crude reaction mixture was basified with saturatedsodium bicarbonate and extracted into ethyl acetate. The ethyl acetatesolution was dried over sodium sulfate, filtered, and concentrated. Thecrude product was purified by elution through a silica gel column with agradient of 0-20% methanol in ethyl acetate to give 36.9 mg oftert-butyl(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate.

tert-butyl(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicarbamate(514 mg, 0.75 mmol) was treated with 10 mL of 1.25N hydrogen chloride inethanol and warmed to 40° C. for 3 hours, then stirred at roomtemperature overnight. The crude reaction mixture was concentrated thendried under high vacuum for 5 hours to give 483 mg of(2R,2′R)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-amino-2-phenylethanone)tetrahydrochlorideas an amber solid.

(2R,2′R)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-amino-2-phenylethanone)tetrahydrochloride(25 mg, 0.028 mmol), picolinic acid (8 mg, 0.063 mmol) and2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (27 mg, 0.070 mmol) were combined with 1 mL of 10%N,N-diisopropylethyl amine in DMF and stirred at room temperature untilcomplete by LCMS. The crude reaction mixture was diluted with 0.5 mLeach of formic acid, water, and acetonitrile, filtered through a 0.2 msyringe filter and purified by reverse phase HPLC using a gradient of10-41% organic phase. Lyophilization gaveN,N′-(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dipicolinamideas the trifluoroacetate salt, 13.8 mg.

LCMS-ESI⁺: calc'd for C₅₆H₄₈N₁₀O₆: 956.38 (M⁺). Found: 957.8 (M+H⁺).

Example LL-1

(2R,2′R)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-amino-2-phenylethanone)tetrahydrochloride(20 mg, 0.022 mmol), pyrimidine-4-carboxylic acid (7 mg, 0.06 mmol) and2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (30 mg, 0.073 mmol) were combined with 1 mL of 10%N,N-diisopropylethyl amine in DMF and stirred at room temperature untilcomplete by LCMS. The crude reaction mixture was diluted with 0.5 mLeach of formic acid, water, and acetonitrile, filtered through a 0.2 μmsyringe filter and purified by reverse phase HPLC using a gradient of10-52% organic phase. Lyophilization gaveN,N′-(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dipyrimidine-4-carboxamideas the trifluoroacetate salt, 2.5 mg.

LCMS-ESI⁺: calc'd for C₅₄H₄₆N₁₂O₆: 958.37 (M⁺). Found: 959.7 (M+H⁺).

Example LM

To a solution of(2R,2′R)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-amino-2-phenylethanone)tetrahydrochloride (24 mg, 0.027 mmol) and N,N-diisopropylethyl amine(281 L, 0.162 mmol) in dimethylformamide (300 μL) was added cyclopropanecarbonyl chloride (5.5 mg, 0.053 mmol). The reaction was stirred at roomtemperature for 3 hours. The crude reaction mixture was diluted with 10drops of formic acid, 5 drops of water, and methanol to a total volumeof 1.2 mL, filtered through a 0.2 μm syringe filter and purified byreverse phase HPLC using a gradient of 10-60% organic phase.Lyophilization gave N,N′-(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicyclopropanecarboxamideas the trifluoroacetate salt, 6.3 mg.

LCMS-ESI⁺: calc'd for C₅₂H₅₀N₈O₆: 882.39 (M⁺). Found: 883.8 (M+H⁺).

Example LN

To a solution of(2R,2′R)-1,1′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-amino-2-phenylethanone)tetrahydrochloride(24 mg, 0.027 mmol) and N,N-diisopropylethyl amine (28 μL, 0.162 mmol)in dimethylformamide (300 μL) was added cyclobutane carbonyl chloride(6.0 mg, 0.053 mmol). The reaction was stirred at room temperature for 3hours. The crude reaction mixture was diluted with 10 drops of formicacid, 5 drops of water, and methanol to a total volume of 1.1 mL,filtered through a 0.2 μm syringe filter and purified by reverse phaseHPLC using a gradient of 10-46% organic phase. Lyophilization gaveN,N′-(1R,1′R)-2,2′-((2S,2′S)-2,2′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(2-oxo-1-phenylethane-2,1-diyl)dicyclobutanecarboxamideas the trifluoroacetate salt, 4.5 mg.

LCMS-ESI⁺: calc'd for C₅₄H₅₄N₈O₆: 910.42 (M⁺). Found: 911.9 (M+H⁺).

Example LO

(S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate

To a solution of 2-bromo-1-(4-bromophenyl)ethanone (2.3 g, 8.39 mmol)and(S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (2.61 g, 10.06 mmol) in MeCN (100 mL) was added Et₃N (1.26 mL, 9.24mmol). After stirring over night, the solution was diluted with EtOAc,washed with sat. NaHCO₃, brine, dried with MgSO₄, and concentrated. Theresidue was purified by silica gel chromatography to yield product (3.32g).

(2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl4-(methoxymethyl) pyrrolidine-1,2-dicarboxylate (3.32 g, 7.27 mmol) inPhMe (100 mL) was added NH₄OAc (11.2 g, 145.5 mmol). The solution washeated to reflux over night. The solution was cooled, and diluted withEtOAc, washed with H₂O, sat. NaHCO₃, brine, dried with MgSO₄, andconcentrated. The residue was purified by silica gel chromatography toyield product (1.46 g).

(2S,4S)-tert-butyl-2-(5-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

(2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(520 mg, 1.19 mmol) and methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(651 mg, 1.31 mmol) were combined in DME (12 mL). Pd(PPh₃)₄ (138 mg,0.12 mmol), Pd(dppf)₂Cl₂ (88 mg, 0.12 mmol) and K₂CO₃ (2M H₂O, 1.96 mL,3.9 mmol) were added, and the solution was degassed with N₂ for 10 min.The solution was heated to 85° C. and stirred for 5 hours. After coolingto rt, the solution was diluted with EtOAc, washed with sat. NaHCO₃,brine, dried with MgSO₄, and concentrated. The residue was purified bysilica gel chromatography to yield product (387 mg).

2-(5-(4′-(2-((2S,4S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-4-((methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-yl)butan-2-ylcarbamate

To(2S,4S)-tert-butyl-2-(5-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(187 mg, 0.26 mmol) in DCM (5 mL) and MeOH (1 mL) was added HCl (4M indioxane, 1.5 mL). The solution stirred for 4 h, and the solvent wasremoved. The intermediate was dissolved in DMF (3 mL).(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (54 mg, 0.26 mmol),COMU (124 mg, 0.26 mmol), and DIPEA (0.23 mL, 1.3 mmol) were addedsequentially. The solution stirred o/n and the mixture was purified byHPLC to yield product (58.8 mg). LCMS-ESI⁺: calc'd for C₄₇H₅₀N₈O₇:816.94 (M⁺). Found: 817.34 (M+H⁺).

Example LP

Methyl-(S)-1-((S)-2-(5-(4′-(2-((2S,4S)-(tert-butyl)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

To(2S,4S)-tert-butyl-2-(5-(4′-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(191 mg, 0.26 mmol) in DCM (5 mL) and MeOH (1 mL) was added HCl (4M indioxane, 1.0 mL). The solution stirred for 16 h, and the solvent wasremoved. The intermediate was dissolved in DMF (5 mL).(R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (65 mg, 0.26 mmol),COMU (124 mg, 0.26 mmol), and DIPEA (0.23 mL, 1.3 mmol) were addedsequentially. The solution stirred for 2 h., diluted with MeOH/EtOAc(1:10), washed with sat. NaHCO₃ twice, brine, dried over MgSO₄ andconcentrated. It was purified by silica gel chromatography to yieldproduct (187 mg).

Methyl(S)-1-((S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

To methyl(S)-1-((S)-2-(5-(4′-(2-((2S,4S)-(tert-butyl)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(187 mg, 0.22 mmol) in DCM (5 mL) and MeOH (1 mL) was added HCl (4M indioxane, 1.0 mL). The solution was stirred for 16 h, and the solvent wasremoved. The intermediate was dissolved in DMF (5 mL).Cyclopropanecarboxylic acid (34 μL, 0.44 mmol), COMU (104 mg, 0.22mmol), and DIPEA (0.19 mL, 1.09 mmol) were added sequentially. Thesolution stirred for 30 min. It was purified by HPLC to yield product(66.5 mg). LCMS-ESI⁺: calc'd for C₄₇H₅₀N₈O₇: 826.98 (M⁺). Found: 827.37(M+H⁺).

Example LQ

7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one

To a stirred solution of 7-hydroxy-1-tetralone (13.9 g, 85.7 mmol) and1-bromo-2-(bromomethyl)-4-chlorobenzene (25.6 g, 90.0 mmol) indimethylformamide (850 mL) was added potassium carbonate (24 g, 172mmol). The reaction was stirred under argon for 18 hours then dilutedwith ethyl acetate (1 L). The organics were washed three times withwater and once with brine. The organic layer was then dried withmagnesium sulfate, filtered and concentrated. To the resulting oil wasadded methanol (500 mL) and the suspension was agitated for thirtyminutes. 7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one(27.8 g, 89% yield) was isolated by filtration.

3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one

To a 1 L flask containing palladium(II) pivalate (1.18 g, 3.8 mmol),tri(4-fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g,22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added asolution of7-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (27.8 g,76.2 mmol) in dimethyacetamide (380 mL). The flask was evacuated andbackfilled with argon 5 times and then stirred under argon at 60° C. for24 hours. The reaction was cooled to room temperature and diluted withMTBE and water. The resulting biphasic mixture was stirred for 3 hoursand filtered through Celite, rinsing with MTBE. The organic layer of thefiltrate was separated and then washed twice with water and once withbrine. The organics were then dried with magnesium sulfate, filtered,concentrated and purified by flash column chromatography (Hexanes/DCM)to yield 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4g, 67% yield) as an off-white solid.

9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one

To a mixture of 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(14.8 g, 52 mmol) in chloroform (50 mL) and ethyl acetate (50 mL) wasadded copper(II) bromide (24.3 g, 104 mmol). The reaction was heated to80° C. for 2 hours and then cooled to room temperature. The mixture wasdiluted with dichloromethane and washed twice with a 5:1 solution ofsaturated aqueous ammonium chloride and aqueous ammonium hydroxide(˜38%), and washed once with water. The organic layer was dried withmagnesium sulfate, filtered and concentrated to yield9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (18.5g, >95% yield) with >95% purity.

Note: This reaction is not always this clean. Sometimes there isover-bromination and sometimes there is significant starting material.These impurities can be removed by flash column chromatography.

tert-butyl2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of (1R)-2-(tert-butoxycarbonyl)cyclopentanecarboxylic acid(10.17 g, 47.25 mmol) and 9-bromo-3-chloro10,11-dihydro-6H-naphtho[2,3-c]chromen-8(9H)-one (5.7 mg, 15.7 mmol) inacetonitrile (50 mL) was added diisopropylethylamine (11.11 mL, 64mmol). The reaction was stirred at 50° C. for 4 hours and was thendiluted with ethyl acetate. The organics were washed with water andbrine, dried (MgSO₄) and concentrated. The resulting crude residue waspurified by flash chromatography to yield (2S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-naphtho[c,g]chromen-9-yl)pyrrolidine-1,2-dicarboxylate (4.52 g, 58%). To a solution of(2S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-6H-naphtho[2,3-c]chromen-9-yl)pyrrolidine-1,2-dicarboxylate (3.27 mg, 6.56 mmol) in a mixture oftoluene (11 mL) and 2-methoxyethanol (0.7 mL) was added ammonium acetate(5.06 g, 65.6 mmol). The reaction mixture was heated to 110° C. for 3hours, cooled to room temperature and diluted with ethyl acetate. Theorganics were washed with water and brine, dried (Na₂SO₄), andconcentrated. The crude residue was purified by flash chromatography toyield tert-butyl2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.95 g, 61%). LCMS-ESI⁺: calculated for C27H28ClN₃O3₄₂: 477.98.observed [M+1]⁺: 478.47.

tert-butyl2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of tert-butyl2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.9 g, 3.96 mmol) in dichloromethane (35 mL) was added manganese(IV)oxide (17 g, 198 mmol). The reaction mixture was stirred at roomtemperature for 18 hours, diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield tert-butyl2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.52 g, 81%). LCMS-ESI⁺: calculated for C27H26ClN3O3₄₂: 475.9. observed[M+1]⁺: 476.45.

tert-butyl2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

A degassed mixture of tert-butyl2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.52 g, 3.17 mmol), bis(pinacolato)diboron (1.21 g, 4.75 mmol),potassium acetate (934 mg, 9.52 mmol),tris(dibenzylideneacetone)palladium (116 mg, 0.13 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (121 mg,0.08 mmol) in 1,4-dioxane (16 mL) was heated to 90° C. for 1.5 hours,cooled to room temperature and diluted with ethyl acetate. The organicswere washed with water and brine, dried (Na₂SO₄), and concentrated. Thecrude residue was purified by flash chromatography to yield tert-butyl2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(1.7 g, 94%).

tert-butyl2-[9-(2-{1-[N-(methoxycarbonyl)valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

To a solution of methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(1.48 g, 3.97 mmol), tert-butyl2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(1.88 g, 1.48 mmol), tetrakis(triphenyl phosphine)palladium(0) (191 mg,0.16 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (242 mg, 0.33 mmol) in a mixture of1,2-dimethoxyethane (37.0 mL) and dimethylformamide (6 mL) was added asolution of potassium carbonate (2M in water, 5 mL, 9.93 mmol). Theresulting mixture was degassed and then heated to 85° C. under argon for18 hours. After cooling to room temperature, the reaction was dilutedwith ethyl acetate. The organics were washed with water and brine, dried(Na₂SO₄), and concentrated. The crude residue was purified by flashchromatography to yield tert-butyl2-[9-(2-{1-[N-(methoxycarbonyl)valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(1.45 mg, 59%). LCMS-ESI⁺: calculated for C41H47N7O6₇₃ 733.86. observed[M+1]⁺: 734.87.

[1-(2-{5-[2-(1-{[(methoxycarbonyl)amino](phenyl)acetyl}pyrrolidin-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl]carbamicacid

A solution of tert-butyl2-[9-(2-{1-[N-(methoxycarbonyl)valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(462 mg, 0.63 mmol), ethanol (6 mL) and concentrated HCl (2 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (172 mg, 0.82 mmol) andCOMU (311 mg, 073 mmol) in DMF (6 mL). To the resulting solution wasadded diisopropylethylamine (330 μL, 1.89 mmol). After stirring for 18hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give[1-(2-{5-[2-(1-{[(methoxycarbonyl)amino](phenyl)acetyl}pyrrolidin-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl]carbamnicacid (231 mg, 45%). LCMS-ESI⁺: calculated for C46H48N8O7₈: 824.92.observed [M+1]⁺: 826.00.

Example LR

(2S,4S)-1-tert-butyl 2,4-dimethyl pyrrolidine-1,2,4-tricarboxylate

To a solution of (2S,4S)-1-tert-butyl 2-methyl4-cyanopyrrolidine-1,2-dicarboxylate (9.0 g, 35.4 mmol) in MeOH (196 mL)was added HCl (4M in 1,4-dioxane, 100 mL, 403 mmol). The solution wasstirred at room temperature for 16 h and concentrated in vacuo. Thecrude intermediate was dissolved in EtOAc (180 mL) and basified withaqueous bicarbonate (sat.). Di-tert-butyl dicarbonate (8.5 g, 38.9 mmol)was added and the biphsic solution was stirred at room temperature for12 h. The layers were then separated and the aqueous layer wasbackextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated. The crude oil was purifiedby silica gel chromatography (15% to 40% to 100% EtOAc/Hexanes) toprovide (2S,4S)-1-tert-butyl 2,4-dimethylpyrrolidine-1,2,4-tricarboxylate (9.56 g, 94%).

(3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-3-carboxylicacid

To a solution of (2S,4S)-1-tert-butyl 2,4-dimethylpyrrolidine-1,2,4-tricarboxylate (9.56 g, 33.3 mmol) in THF (70 mL) at0° C. (external temperature, ice bath) was added NaOH (1N aqueous, 33mL, 33.3 mmol) dropwise over 15 min. The solution was stirred at 0° C.for 5 h before acidification with HCl (1N). The solution was extractedwith EtOAc (3×). The combined organic layers were dried over Na₂SO₄ andconcentrated. The crude oil was purified by silica gel chromatography(2% to 5% to 10% MeOH/CH₂Cl₂) to provide(3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-3-carboxylicacid (6.38g, 70%).

(2S,4S)-1-tert-butyl 2-methyl4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate

To a solution of(3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-3-carboxylicacid (6.38 g, 23.3 mmol) in THF (116 mL) at 0° C. (external temperature,ice bath) was added Et₃N (4.9 mL, 35.0 mmol) and ethyl chloroformate(2.7 mL, 28.0 mmol). The resulting solution was stirred at 0° C. for 45min, during which time a white precipitate forms. The reaction mixturewas filtered through celite and concentrated.

The crude intermediate was dissolved in THF (59 mL) and cooled to 0° C.(external temperature, ice bath). NaBH₄ (4.41 g, 116.7 mmol) in H₂O (59mL) was slowly added and the resulting solution was stirred at 0° C. for2 h. The reaction mixture was diluted with EtOAc and washed with H₂O.The aqueous layer was backextracted with EtOAc. The combined organiclayers were dried over Na₂SO₄ and concentrated. The crude oil waspurified by silica gel chromatography (42% to 69% to 100% EtOAc/Hexanes)to provide (2S,4S)-1-tert-butyl 2-methyl4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.63 g, 60%).

(2S,4S)-1-tert-butyl 2-methyl4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate

To a solution of (2S,4S)-1-tert-butyl 2-methyl4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (2.57 g, 9.9 mmol) inCH₂Cl₂ (50 mL) was added AgOTf (4.07 g, 15.8 mmol) and2,6-di-tert-butylpyridine (4.4 mL, 19.8 mmol). The reaction mixture wascooled to 0° C. (external temperature, ice bath) and MeI (0.98 mL, 15.8mmol) was slowly added. The resulting slurry was stirred at 0° C. for1.5 h and at room temperature for 1.5 h. The slurry was diluted withCH₂Cl₂ and filtered through celite. The filtrate was concentrated todryness, dissolved in Et₂O, and washed with HCl (1N) and brine. Theaqueous layers were backextracted with Et₂O and the combined organiclayers were dried over Na₂SO₄ and concentrated. The crude oil waspurified by silica gel chromatography (10% to 75% to 100% EtOAc/Hexanes)to provide (2S,4S)-1-tert-butyl 2-methyl4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.11 g, 78%). ¹H-NMR:400 MHz, (CDCl₃) δ: (mixture of rotomers, major reported) 4.20 (t, 1H),3.71 (s, 3H), 3.67 (m, 1H), 3.34 (m, 2H), 3.30 (s, 3H), 3.16 (t, 1H),2.43 (m, 2H), 1.74 (m, 1H), 1.38 (s, 9H).

(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid

To a solution of (2S,4S)-1-tert-butyl 2-methyl4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.11 g, 7.7 mmol) in amixture of THF (38 mL) and McOH (15 mL) was added LiOH (2.5 M aqueous,15 mL, 38.6 mmol). The resulting solution was stirred at roomtemperature for 2 h, and acidified with aqueous HCl (1N). The desiredproduct was extracted with CH₂C₂ (4×). The combined organic layers weredried over Na₂SO₄ and concentrated to provide(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (2.0 g, 99%). ¹H-NMR: 400 MHz, (CDCl₃) δ: (mixture of rotomers,major reported) 4.33 (t, 1H), 3.65 (m, 1H), 3.35 (m, 2H), 3.32 (s, 3H),3.16 (t, 1H), 2.45 (m, 2H), 2.12 (m, 1H), 1.46 (s, 9H).

Example LR-1

(2S,4S)-tert-butyl-2-(9-chloro-4,5-dihydro-5H-naphtho[2,3-c]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of((S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (5.9 g, 23.1 mmol) and9-bromo-3-chloro-10,11-dihydro-5H-naphtho[c,g]chromen-8(9H)-one (5.6 mg,15.4 mmol) in acetonitrile (60 mL) was added diisopropylethylamine (5.35mL, 30.8 mmol). The reaction was stirred at 50° C. for 18 hours and wasthen diluted with ethyl acetate. The organics were washed with water andbrine, dried (MgSO₄) and concentrated. The resulting crude residue waspurified by flash chromatography to yield(2S)-1-tert-butyl-2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-6H-naphtho[2,3-c]chromen-9-yl)-4(methoxymethyl)pyrrolidine-1,2-dicarboxylate (5.12 g, 61%). To a solution of(2S)-1-tert-butyl-2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-6H-naphtho[2,3-c]chromen-9-yl)-4(methoxymethyl)pyrrolidine-1,2-dicarboxylate(5.11 mg, 9.42 mmol) in a mixture of toluene (94 mL) and2-methoxyethanol (0.1 mL) was added ammonium acetate (23.5 g, 304 mmol).The reaction mixture was heated to 110° C. for 18 hours, cooled to roomtemperature and diluted with ethyl acetate. The organics were washedwith water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield (2S,4R)-tert-butyl2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(1.05g, 21%) and(2S,4S)-tert-butyl-2-(9-chloro-4,5-dihydro-6H-naphtho[2,3-c]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(2.0 g, 41%). LCMS-ESI⁺: calculated for C₂₉H₃₂ClN₃O₄₂: 522.0. observed[M+1]⁺: 522.2.

(2S,4S)-tert-butyl-2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of(2S,4S)-tert-butyl-2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(1.99 g, 3.82 mmol) in dichloromethane (30 mL) was added manganese(IV)oxide (10 g, 115 mmol). The reaction mixture was stirred at roomtemperature for 18 hours, diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO4), and concentrated. The cruderesidue was purified by flash chromatography to yield(2S,4S)-tert-butyl-2-(9-chloro-6H-naphtho[2,3-c]chromeno[8,9-d]imidazol-2-yl)-4-methoxymethyl)pyrrolidine-1-carboxylate(1.05g, 21%) and(2S,4S)-tert-butyl-2-(9-chloro-4,5-dihydro-6H-naphtho[2,3-c]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(1.64 g, 82%). LCMS-ESI⁺: calculated for C₂₉H₃₀ClN₃O₄₂: 520.02. observed[M+1]⁺: 520.97.

(2S,4S)-tert-butyl-4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)pyrrolidine-1-carboxylate

A degassed mixture of-(2S,4S)-tert-butyl-2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (649 mg 1.25 mmol), bis(pinacolato)diboron(635 mg, 2.5 mmol), potassium acetate (368 mg, 3.7 mmol),tris(dibenzylideneacetone)palladium (46 mg, 0.05 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (60 mg, 0.12mmol) in 1,4-dioxane (7 mL) was heated to 90° C. for 3 hours, cooled toroom temperature and diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)pyrrolidine-1-carboxylate (467 mg, 61%) LCMS-ESI⁺: calculated forC₃₅H₄₂BN₃O₆: 611.54; observed [M+1]⁺: 612.96.

(2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)pyrrolidine-1-carboxylate(467 mg, 0.76 mmol), methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(342 mg, 0.92 mmol), tetrakis(triphenylphosphine) palladium(0) (44 mg,0.04 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (56 mg, 0.07mmol) in a mixture of 1,2-dimethoxyethane (11.0 mL) anddimethylformamide (1.9 mL) was added a solution of potassium carbonate(2M in water, 1.15 mL, 2.29 mmol). The resulting mixture was degassedand then heated to 85° C. under argon for 18 hours. After cooling toroom temperature, the reaction was diluted with ethyl acetate. Theorganics were washed with water and brine, dried (Na₂SO₄), andconcentrated. The crude residue was purified by flash chromatography toyield (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(180 mg, 67%). LCMS-ESI⁺: calculated for C₄₃H₅₁N₇O₇₃ 777.91. observed[M+1]⁺: 778.84.

methyl{2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A solution of (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(196 mg, 0.25 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (69 mg, 0.33 mmol) andCOMU (124 mg, 029 mmol) in DMF (4 mL). To the resulting solution wasadded diisopropylethylamine (130 μL, 0.76 mmol). After stirring for 2hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give methyl{2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(84 mg, 39%). LCMS-ESI⁺: calculated for C₄₈H₅₂N₈O₈: 868.98. observed[M+1]⁺: 870.11.

Example LS

methyl{1-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A solution of (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(116 mg, 0.15 mmol), ethanol (5 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (10 mL). This solution was concentrated and tothis material was added a solution of2-methoxycarbonylamino-3-methylbutyric acid (38 mg, 0.22 mmol) and HATU(79 mg, 0.21 mmol) in DMF (1.4 mL). To the resulting solution was addeddiisopropylethylamine (270 μL, 1.5 mmol). After stirring for 18 hours atroom temperature, the reaction was diluted with ethyl acetate, washedwith water and brine, dried (Na₂SO₄), concentrated and purified bypreparative reverse phase HPLC (Gemini, 15 to 45% ACN/H₂O+0.1% TFA). Theproduct fractions were lyophilized to give methyl{1-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(58 mg, 13%). LCMS-ESI⁺: calculated for C₄₅H₅₄N₈O₈: 834.96. observed[M+1]⁺: 835.70.

Example LT

(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)pyrrolidine-1-carboxylate(557 mg, 0.91 mmol), methyl (S)-1-((1S,3S,5S)-3-(5-bromo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(350 mg, 0.91 mmol) tetrakis(triphenylphosphine) palladium(0) (53 mg,0.04 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (67 mg, 0.07mmol) in a mixture of 1,2-dimethoxyethane (11.0 mL) anddimethylformamide (1.9 mL) was added a solution of potassium carbonate(2M in water, 1.37 mL, 2.7 mmol). The resulting mixture was degassed andthen heated to 85° C. under argon for 18 hours. After cooling to roomtemperature, the reaction was diluted with ethyl acetate. The organicswere washed with water and brine, dried (Na₂SO₄), and concentrated. Thecrude residue was purified by flash chromatography to yield(2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(271 mg, 38%). LCMS-ESI⁺: calculated for C44H51N7O7. 789.92. observed[M+1]⁺: 790.76.

methyl{2-[2-{9-[2-(2-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A solution of (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(196 mg, 0.25 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (69 mg, 0.33 mmol) andCOMU (124 mg, 029 mmol) in DMF (4 mL). To the resulting solution wasadded diisopropylethylamine (130 μL, 0.76 mmol). After stirring for 2hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give methyl{2-[2-{9-[2-(2-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(84 mg, 39%). LCMS-ESI⁺: calculated for C49H52N8O8: 880.99. observed[M+1]⁺: 882.09.

Example LU

(1R,3S,5R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

To a solution of(1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (3.0 g, 13.5 mmol), 6-bromonaphthalene-1,2-diamine (3.1 g, 13.1mmol), and HATU (5.6 g, 14.7 mmol) in CH₂Cl₂ (125 mL) was added DIPEA(10.8 mL, 61.8 mmol). The solution was stirred at room temperature for 4hour and concentrated to dryness. The crude oil was dissolved in EtOAcand washed with water and brine. The aqueous layers were backextractedwith EtOAc, and the combined organic layers were dried over Na₂SO₄ andconcentrated to dryness. The crude oil was purified by silica gelchromatography (20 to 100% EtOAc(5% MeOH)/Hexanes).

The resulting intermediate was dissolved in AcOH (125 mL), and stirredat room temperature for 18 h. The solution was concentrated and thecrude oil was dissolved in EtOAc. The solution was washed with aqueousbicarbonate (sat.) and brine. The aqueous layers were backextracted withEtOAc and the combined organic layers were dried over Na₂SO₄ andconcentrated. The crude oil was purified by silica gel chromatography (2to 5% MeOH/CH₂Cl₂) to provide (1R,3S,5R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(5.08 g, 91%). LCMS-ESI⁺: calc'd for C₂₁H₂₂BrN₃O₂: 427.09 (M⁺). Found:428.71 (M+H⁺).

(1R,3S,5R)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

To a solution of (1R,3S,5R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.06 g, 4.8 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.84, 7.2mmol), KOAc (1.41 g, 14.4 mmol) in 1,4-dioxane (50 mL) was addedPd(dppf)Cl₂ (0.18 g, 0.3 mmol). The slurry was degassed with argon for 5min and heated to 80° C. (external temperature, oil bath). The reactionwas stirred at 80° C. for 5 h, and then cooled to room temperature for15 h. The solution was diluted with EtOAc and filtered through celite.After concentration of the solution, the crude oil was purified twice bysilica gel chromatography (first column: 25 to 100% EtOAc(5%MeOH)/Hexanes); second column: 2 to 5% MeOH/CH₂Cl₂) to provide (1R,3S,5R)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.17 g, 95%). LCMS-ESI⁺: calc'd for C₂₇H₃₄BN₃O₄: 475.26 (M⁺). Found:476.11 (M+H⁺).

methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate

To a solution of (1R,3S,5R)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(0.60 g, 1.3 mmol) in a mixture of CH₂Cl₂ (12.0 mL) and MeOH (2.5 mL)was added HCl (4M in 1,4-dioxane, 9.4 mL, 37.6 mmol). The solution wasstirred at room temperature for 2.5 h and concentrated to dryness. Thecrude intermediate was suspended in CH₂Cl₂ (12 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.25 g, 1.4 mmol),HATU (0.58 g, 1.5 mmol), and DIPEA (0.7 mL, 4.0 mmol) were sequentiallyadded to the reaction. The homogenous solution was then stirred at roomtemperature for 1.5 h. The solution was diluted with CH₂Cl₂ and washedwith HCl (aqueous, 1N) and aqueous bicarbonate (sat.). The aqueouslayers were backextracted with CH₂Cl₂ and the combined organic layerswere dried over Na₂SO₄ and concentrated. The crude oil was then purifiedby silica gel chromatography (30 to 100% EtOAc(5% MeOH)/Hexanes) toprovide methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate(0.60 g, 89%). LCMS-ESI⁺: calc'd for C₂₉H₃₇BN₄O₅: 532.29 (M⁺). Found:533.11 (M+H⁺).

(2S,4S)-tert-butyl2-(2′-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate(0.60 g, 1.1 mmol) and (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.46 g, 1.0 mmol) in DME (5 mL) was added Pd(PPh₃)₄ (0.08 g, 0.07 mmol)and K₃PO₄ (2M aqueous, 1.5 mL, 3.0 mmol). The resulting solution wasdegassed with argon for 5 min and heated to 80° C. (externaltemperature, oil bath) for 18 h. The reaction mixture was then cooled toroom temperature and diluted with MeOH and CH₂Cl₂. The solution waswashed with H₂O and brine, and the aqueous layers were backextractedwith CH₂Cl₂ and MeOH (˜10:1). The organic layers were combined and driedover Na₂SO₄ and concentrated. The crude oil was purified by silica gelchromatography (30 to 100% EtOAc(10% MeOH)/Hexanes to 80% MeOH/EtOAc) toprovide (2S,4S)-tert-butyl2-(2′-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.79 g, 71%). LCMS-ESI⁺: calc'd for C₄₅H₅₁N₇O₆: 785.39 (M⁺). Found:786.61 (M+H⁺).

methyl(R)-2-((2S,4S)-4-(methoxymethyl)-2-(2′-((1R,3S,5R)-2-((S)-3-methyl-2-methoxycarbonylaminobutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

To a solution of (2S,4S)-tert-butyl 2-(2′-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.40 g, 0.5 mmol) in a mixture of CH₂Cl₂ (6.0 mL) and MeOH (1.0 mL) wasadded HCl (4M in 1,4-dioxane, 2.5 mL, 10.0 mmol). The solution wasstirred at room temperature for 2.5 h and concentrated to dryness. Thecrude intermediate was purified by preparative HPLC (Gemini column,10-50% MeCN/H₂O with 0.1% TFA). The combined fractions were basifiedwith aqueous bicarbonate (sat.) and diluted with brine. The desiredproduct was extracted with CH₂Cl₂ (3×). The combined organic layers weredried over Na₂SO₄ and concentrated.

The intermediate was dissolved in CH₂Cl₂ (2.5 mL).(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.045 g, 0.21 mmol)and DIPEA (0.05 mL, 0.28 mmol) were then added to the solution. Thereaction mixture was cooled to −40° C. (external temperature,MeCN/CO₂(s) bath). COMU (0.098 g, 0.23 mmol) was then added and solutionwas allowed to warm to 0° C. over 1 h. The solution was diluted with DMFand concentrated. The crude product was purified by preparative HPLC(Gemini column, 10-60% MeCN/H₂O with 0.1% TFA) and the desired fractionswere combined. The solution was concentrated until the aqueous layerremained and aqueous bicarbonate (sat.) was slowly added until thesolution was basic. The resulting slurry was stirred at room temperaturefor 2 h and filtered. The resulting solid was dried in vacuo to providemethyl(R)-2-((2S,4S)-4-(methoxymethyl)-2-(2′-((1R,3S,5R)-2-((S)-3-methyl-2-methoxycarbonylaminobutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(0.14 g, 75%). LCMS-ESI⁺: calc'd for C₅₀H₅₂N₈O₇: 876.40 (M⁺). Found:877.82 (M+H⁺).

Example LV

(2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methylthio)pyrrolidine-1-carboxylatewas synthesized using methods analogous to the preparation of(S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate,substituting(2S,4S)-1-(tert-butoxycarbonyl)-4-(methylthio)pyrrolidine-2-carboxylicacid for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid.(2S,4S)-1-(tert-butoxycarbonyl)-4-(methylthio)pyrrolidine-2-carboxylicacid is a known compound and may be prepared by one of the methodsdescribed in the following literature: J. Med. Chem. 38(1996), 137-149;Bioorganic & Medicinal Chemistry 14(2006), 2253-2265.

To (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methylthio)pyrrolidine-1-carboxylate(23 mg, 0.05 mmol), (S)-tert-butyl2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(30 mg, 0.06 mmol), Pd(PPh₃)₄ (9 mg, 0.008 mmol). DME (0.5 mL) was addedand followed by 0.25 mL 1M NaHCO₃ aqueous solution. The reaction waspurged with Ar and heated to 120° C. at microwave synthesizer for 0.5hour. The reaction was cooled to room temperature and concentrated down.EtOAc was added and washed with sat. NaHCO₃ aqueous (2×) and sat. NaClaqueous (1×). The organic layer was concentrated down after drying oversodium sulfate and subject to reverse phase prep.HPLC to provideIntermediate LV1 (5.5 mg, 15%). MS (ESI) m/z 719 [M+H]⁺.

To tert-butyl(2S,4S)-2-{2′-[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methylsulfanyl)pyrrolidine-1-carboxylate(5 mg, 0.007 mmol) in dichloromethane (0.1 mL) was added 4M HCl indioxane (0.1 mL) and the reaction mixture was cooled to 0° C. and thenstirred for 2 hours. The reaction was then concentrated in vacuo toafford the HCl salt.

To the HCl salt in DMF (0.15 mL) was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (2.8 mg, 0.016 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.8 mg,0.015 mmol) and hydroxybenzotriazole hydrate (HOBt), (2 mg, 0.015 mmol).The mixture was cooled down in an ice bath to 0° C. andN-methylmorpholine (NMM)(4 μL, 0.035 mmol) was added from a syringe tothe mixture. The reaction content was stirred for 4 hours at roomtemperature. The resulting mixture was then directly purified on reversephase prep.HPLC to afford methyl{(2S)-1-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methylsulfanyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamateas white solid (3.5 mg, 60%). MS (ESI) m/z 833.35 [M+H]⁺.

Example LW

(S)-1-((S)-2-(7-(5,6-bis(tert-butoxycarbonylamino)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester

To methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(190 mg, 0.36 mmol), tert-butyl 6-bromonaphthalene-1,2-diyldicarbamate(205 mg, 0.47 mmol), Pd(PPh₃)₄ (42 mg, 0.036 mmol). DME (1.5 mL) wasadded and followed by 1.08 mL 1M NaHCO₃ aqueous solution. The reactionwas purged with Ar and heated to 120° C. at microwave synthesizer for0.5 hour. The reaction was cooled to room temperature and concentrateddown. EtOAc was added and washed with sat. NaHCO₃ aqueous (2×) and sat.NaCl aqueous (1×). The organic layer was concentrated down after dryingover sodium sulfate and subject to silica gel chromatography with aneluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCOcolumn (12 g silica gel). The fractions containing product were combinedand the solvent was removed under reduced pressure to provide thedesired product (205 mg, 75%). MS (ESI) m/z 752 [M+H]⁺.

Methyl(S)-1-((S)-2-(7-(5,6-diaminonaphthalene-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

To(S)-1-((S)-2-(7-(5,6-bis(tert-butoxycarbonylamino)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamicacid methyl ester (165 mg, 0.22 mmol) in dichloromethane (2.2 mL) wasadded TFA (0.5 mL) and the reaction mixture stirred for 2 hours. Thesolvent was removed under reduced pressure to provide title compound asTFA salts.

(2S,4S)-tert-butyl2-(1-amino-6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-ylcarbamoyl)-4-(methylthio)pyrrolidine-1-carboxylate

To above TFA salts in DCM (2 mL) was added(2S,4S)-tert-butoxycarbonyl)-4-(methylthio)pyrrolidine-2-carboxylic acid(68 mg, 0.26 mmol), HATU (99 mg, 0.26 mmol). The mixture was cooled downin an ice bath to 0° C. and diisopropylethylamine (192 μL, 1.1 mmol) wasadded from a syringe to the mixture. The reaction mixture was stirredfor 0.5 hours at room temperature. EtOAc was added and washed with sat.NaHCO₃ aqueous (2×) and sat. NaCl aqueous (1×). The organic layer wasconcentrated down after drying over sodium sulfate and subject to silicagel chromatography with an eluent of ethyl acetate and hexane at agradient of 40-100% with an ISCO column (12 g silica gel). The fractionscontaining product were combined and the solvent was removed underreduced pressure to provide title compound (122 mg, 70%). MS (ESI) m/z795 [M+H]⁺.

tert-butyl(2S,4S)-2-(2′-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methylsulfanyl)pyrrolidine-1-carboxylate

To (2S,4S)-tert-butyl2-(1-amino-6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-ylcarbamoyl)-4-(methylthio)pyrrolidine-1-carboxylate (95mg, 0.12 mmol) in acetic acid (4 mL) and the reaction mixture stirredfor 16 hours. Concentrated in vacuo and diluted with EtOAc, washed withsat. NaHCO₃ aqueous (2×) and sat. NaCl aqueous (1×). The organic layerwas concentrated down after drying over sodium sulfate and subject tosilica gel chromatography with an eluent of ethyl acetate and hexane ata gradient of 40-100% with an ISCO column (12 g silica gel). Thefractions containing product were combined and the solvent was removedunder reduced pressure to provide tert-butyl (2S,4S)-2-(2′-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methylsulfanyl)pyrrolidine-1-carboxylate(50 mg, 54%). MS (ESI) m/z 777 [M+H]⁺.

methyl{(1R)-2-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methylsulfanyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

To tert-butyl(2S,4S)-2-(2′-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methylsulfanyl)pyrrolidine-1-carboxylate(15 mg, 0.02 mmol) in methanol (0.1 mL) was added 4M HCl in dioxane (0.1mL) and the reaction mixture was stirred for 2 hours. After concentratedin vacuum to afford HCl salts.

This HCl salts in DMF (0.2 mL) was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (5 mg, 0.024 mmol),COMU (10 mg, 0.024 mmol) and the mixture was cooled down in an ice bathto 0° C. and diisopropylethylamine (11 μL, 0.06 mmol) was added from asyringe to the mixture. The reaction mixture was stirred for 1 hour atroom temperature. The resulting mixture was then directly purified onreverse phase prep.HPLC to afford methyl{(1R)-2-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methylsulfanyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamateas white solid (8 mg, 50%). MS (ESI) m/z 867.58[M+H]⁺.

Example LX

(1R,3S,5R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

To a solution of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid (3.0 g, 13.5 mmol), 6-bromonaphthalene-1,2-diamine (3.1 g, 13.1mmol), and HATU (5.6 g, 14.7 mmol) in CH₂Cl₂ (125 mL) was added DIPEA(10.8 mL, 61.8 mmol). The solution was stirred at room temperature for 4hour and concentrated to dryness. The crude oil was dissolved in EtOAcand washed with water and brine. The aqueous layers were backextractedwith EtOAc, and the combined organic layers were dried over Na₂SO₄ andconcentrated to dryness. The crude oil was purified by silica gelchromatography (20 to 100% EtOAc(5% MeOH)/Hexanes).

The resulting intermediate was dissolved in AcOH (125 mL), and stirredat room temperature for 18 h. The solution was concentrated and thecrude oil was dissolved in EtOAc. The solution was washed with aqueousbicarbonate (sat.) and brine. The aqueous layers were backextracted withEtOAc and the combined organic layers were dried over Na₂SO₄ andconcentrated. The crude oil was purified by silica gel chromatography (2to 5% MeOH/CH₂Cl₂) to provide (1R,3 S,5R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(5.08 g, 91%). LCMS-ESI⁺: calc'd for C₂₁H₂₂BrN₃O₂: 427.09 (M⁺). Found:428.71 (M+H⁺).

(1R,3S,5R)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

To a solution of (1R,3S,5R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.06 g, 4.8 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.84, 7.2mmol), KOAc (1.41 g, 14.4 mmol) in 1,4-dioxane (50 mL) was addedPd(dppf)Cl₂ (0.18 g, 0.3 mmol). The slurry was degassed with argon for 5min and heated to 80° C. (external temperature, oil bath). The reactionwas stirred at 80° C. for 5 h, and then cooled to room temperature for15 h. The solution was diluted with EtOAc and filtered through celite.After concentration of the solution, the crude oil was purified twice bysilica gel chromatography (first column: 25 to 100% EtOAc(5%MeOH)/Hexanes); second column: 2 to 5% MeOH/CH₂Cl₂) to provide (1R,3S,5R)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(2.17 g, 95%). LCMS-ESI⁺: calc'd for C₂₇H₃₄BN₃O₄: 475.26 (M⁺). Found:476.11 (M+H⁺).

methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate

To a solution of (1R,3S,5R)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(0.60 g, 1.3 mmol) in a mixture of CH₂Cl₂ (12.0 mL) and MeOH (2.5 mL)was added HCl (4M in 1,4-dioxane, 9.4 mL, 37.6 mmol). The solution wasstirred at room temperature for 2.5 h and concentrated to dryness. Thecrude intermediate was suspended in CH₂Cl₂ (12 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.25 g, 1.4 mmol),HATU (0.58 g, 1.5 mmol), and DIPEA (0.7 mL, 4.0 mmol) were sequentiallyadded to the reaction. The homogenous solution was then stirred at roomtemperature for 1.5 h. The solution was diluted with CH₂Cl₂ and washedwith HCl (aqueous, 1N) and aqueous bicarbonate (sat.). The aqueouslayers were backextracted with CH₂Cl₂ and the combined organic layerswere dried over Na₂SO₄ and concentrated. The crude oil was then purifiedby silica gel chromatography (30 to 100% EtOAc(5% MeOH)/Hexanes) toprovide methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate(0.60 g, 89%). LCMS-ESI⁺: calc'd for C₂₉H₃₇BN₄O₅: 532.29 (M⁺). Found:533.11 (M+H⁺).

(2S,4S)-tert-butyl2-(2′-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of methyl(S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate(0.60 g, 1.1 mmol) and (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.46 g, 1.0 mmol) in DME (5 mL) was added Pd(PPh₃)₄ (0.08 g, 0.07 mmol)and K₃PO₄ (2M aqueous, 1.5 mL, 3.0 mmol). The resulting solution wasdegassed with argon for 5 min and heated to 80° C. (externaltemperature, oil bath) for 18 h. The reaction mixture was then cooled toroom temperature and diluted with MeOH and CH₂Cl₂. The solution waswashed with H₂O and brine, and the aqueous layers were backextractedwith CH₂Cl₂ and MeOH (˜10:1). The organic layers were combined and driedover Na₂SO₄ and concentrated. The crude oil was purified by silica gelchromatography (30 to 100% EtOAc(10% MeOH)/Hexanes to 80% MeOH/EtOAc) toprovide (2S,4S)-tert-butyl2-(2′-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.79 g, 71%). LCMS-ESI⁺: calc'd for C₄₅H₅₁N₇O₆: 785.39 (M⁺). Found:786.61 (M+H⁺).

methyl(R)-2-((2S,4S)-4-(methoxymethyl)-2-(2′-((1R,3S,5R)-2-((S)-3-methyl-2-methoxycarbonylaminobutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

To a solution of (2S,4S)-tert-butyl 2-(2′-((1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.40 g, 0.5 mmol) in a mixture of CH₂Cl₂ (6.0 mL) and MeOH (1.0 mL) wasadded HCl (4M in 1,4-dioxane, 2.5 mL, 10.0 mmol). The solution wasstirred at room temperature for 2.5 h and concentrated to dryness. Thecrude intermediate was purified by preparative HPLC (Gemini column,10-50% MeCN/H₂O with 0.1% TFA). The combined fractions were basifiedwith aqueous bicarbonate (sat.) and diluted with brine. The desiredproduct was extracted with CH₂Cl₂ (3×). The combined organic layers weredried over Na₂SO₄ and concentrated.

The intermediate was dissolved in CH₂Cl₂ (2.5 mL).(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.045 g, 0.21 mmol)and DIPEA (0.05 mL, 0.28 mmol) were then added to the solution. Thereaction mixture was cooled to −40° C. (external temperature,MeCN/CO₂(s) bath). COMU (0.098 g, 0.23 mmol) was then added and solutionwas allowed to warm to 0° C. over 1 h. The solution was diluted with DMFand concentrated. The crude product was purified by preparative HPLC(Gemini column, 10-60% MeCN/H₂O with 0.1% TFA) and the desired fractionswere combined. The solution was concentrated until the aqueous layerremained and aqueous bicarbonate (sat.) was slowly added until thesolution was basic. The resulting slurry was stirred at room temperaturefor 2 h and filtered. The resulting solid was dried in vacuo to providemethyl(R)-2-((2S,4S)-4-(methoxymethyl)-2-(2′-((1R,3S,5R)-2-((S)-3-methyl-2-methoxycarbonylaminobutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(0.14 g, 75%). LCMS-ESI⁺: calc'd for C₅₀H₅₂N₈O₇: 876.40 (M⁺). Found:877.82 (M+H⁺). ¹H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotomers) 8.57 (m,1H), 8.28 (m, 2H), 7.97 (s, 2H), 7.75 (m, 4H), 7.38 (m, 4H), 5.54 (s,1H), 5.31 (m, 2H), 4.61 (d, 1H), 3.77 (m, 3H), 3.65 (s, 6H), 3.46 (m,1H), 3.32 (s, 3H), 3.20 (m, 2H), 2.57 (m, 3H), 2.17 (m, 1H), 2.06 (m,2H), 1.13 (m, 1H), 1.00 (d, 3H), 0.89 (d, 3H), 0.84 (m, 1H).

Example LY

(1S,3S,4R)-methyl 2-benzyl-2-azabicyclo[2.2.1]heptane-3-carboxylate

(1 S,3 S,4R)-methyl 2-benzyl-2-azabicyclo[2.2.1]heptane-3-carboxylatewas prepared as described in Org Lett 1999, 1, 1595-1597.

(1S,3S,4R)-2-tert-butyl 3-methyl2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate

(1 S,3S,4R)-methyl 2-benzyl-2-azabicyclo[2.2.1]heptane-3-carboxylate(2.9g, 11.82 mmol) and boc anhydride (3.8g, 17.75 mmol) were added to10% palladium on carbon (0.118g) in Ethanol (50 mL). The solution wasstirred under an atmosphere of hydrogen for 16 hours. Upon completion,the reaction was flushed with nitrogen, filtered through a pad ofdiatomaceous earth and purified by normal phase chromatography (12-33%ethyl acetate in hexanes) to give (1S,3S,4R)-2-tert-butyl 3-methyl2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (2.67g, 87%) as a clearoil. ¹H NMR (400 MHz, CDCl₃, mixture of rotomers, major reported) δ 4.36(s, 1H), 4.16 (d, 1H), 3.71 (s, 3H), 2.74 (s, 1H), 1.85-1.73 (m, 1H),1.70-1.54 (m, 2H), 1.48-1.40 (m, 3H), 1.37 (s, 9H).

(1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid

To a solution of (1 S,3 S,4R)-2-tert-butyl 3-methyl2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.67g, 6.54 mmol) inTHF:MeOH (41 mL:13 mL) was added aqueous Lithium hydroxide (1M, 8.2 mL,8.2 mmol) and the reaction was allowed to stir at room temperatureovernight. Upon completion, the reaction was concentrated in vacuo,diluted with ethyl acetate and washed with 1N HCl. The aqueous layer wasbackextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered and concentrated to give(1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (1.36g, 86%). ¹H NMR (400 MHz, Methanol-d4) δ 6.43 (s, 1H), 5.84(s, 1H), 5.74 (d, 1H), 4.34 (s, 1H), 3.36-3.18 (m, 3H), 3.17-3.06 (m,3H), 3.02 (s, 3H), 2.97 (s, 6H).

(1S,3S,4R)-tert-butyl3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

To a solution of 6-bromonaphthalene-1,2-diamine (1.08g, 4.56 mmol), and(1S,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (1.10g, 4.56 mmol) and HATU (2.08g, 5.47 mmol) in methylenechloride (45 mL) was added DIPEA (3.98 mL, 22.79 mmol). The mixture wasstirred at room temperature for two hours. Upon completion, the reactionwas concentrated in vacuo, diluted with ethyl acetate and washed withwater. The aqueous layer was backextracted with ethyl acetate twice. Thecombined organic layers were washed with brine, concentrated, andpurified by normal phase chromatography (30-80% ethyl acetate(5% MeOH)in hexanes) to give (1 S,3 S,4R)-tert-butyl3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(2.01g, 95%). LCMS-ESI⁺: calc'd for C₂₂H₂₆BrN₃O₃: 459.12 (M⁺). Found:460.9 (M+H⁺).

(1S,3S,4R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.11]heptane-2-carboxylate

(1S,3 S,4R)-tert-butyl3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(2.01g, 4.36 mmol) was suspended in AcOH (8.73 mL, 152.7 mmol) andplaced in a preheated 50° C. oil bath. The suspension was let stir at50° C. for 4 hours and at room temperature for 14 hours. Uponcompletion, the reaction mixture was diluted with ethyl acetate andaqueous NaOH (6M, 25.4 mL, 152.7 mmol) was added slowly with stirring.The layers were separated and the aqueous layer was backextracted withethyl acetate twice. The combined organic layers were dried over sodiumsulfate and concentrated in vacuo. The resulting oil was purified bynormal phase chromatography (30-55-100% ethyl acetate(5% MeOH) inhexanes) to give (1 S,3S,4R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(1.8g, 93%). LCMS-ESI⁺: calc'd for C₂₂H₂₄BrN₃O₂: 441.11 (M⁺). Found:442.7 (M+H⁺).

Methyl(S)-1-((1S,3S,4R)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Hydrogen chloride in dioxane solution (4N, 6.78 mL, 27.18 mmol) wasadded to (1S,3S,4R)-tert-butyl3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(0.80g, 1.81 mmol) in methylene chloride: methanol (18.1 mL: 3.6 mL).The suspension was allowed to stir at room temperature for one hour.Upon completion by LCMS, the reaction was concentrated to dryness andthe crude product (assumed 1.81 mmol) was suspended in methylenechloride (18 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(0.38g, 2.17 mmol) and DIPEA (1.58 mL, 9.04 mmol) were added to theslurry. HATU (1.03g, 2.71 mmol) was added and the reaction was stirredat room temperature for 3 hours. Upon completion, the crude reaction wasdiluted in methylene chloride and washed with 1N HCl, and aqueous sodiumbicarbonate. The organic layer was concentrated and purified by normalphase chromatography (40-80% ethyl acetate (5% methanol) in hexanes) togive methyl(S)-1-((1S,3S,4R)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(0.949, >99%).

LCMS-ESI⁺: calc'd for C₂₄H₂₇BrN₄O₃: 498.13 (M⁺). Found: 498.9 (M+H⁺).

(S)-tert-butyl2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

Methyl (S)-1-((1 S,3S,4R)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate(0.300g, 0.601 mmol), (S)-tert-butyl2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(0.334g, 0.721 mmol), and aqueous potassium phosphate (2M, 0.901 mL,1.802 mmol) were suspended in 1,2-dimethoxyethane (3.00 mL) and spargedwith argon gas for 30 minutes. Palladium tetrakis triphenylphosphine(0.069g, 0.060 mmol) was added and the reaction mixture was capped andplaced in a preheated 80° C. oil bath. The solution was heated for 18hours and subsequently stirred at room temperature for two days. Uponcompletion, the reaction was diluted with ethyl acetate and washed withbrine. The concentrated organic layer was purified by normal phasechromatography (40-100% ethyl acetate (10% MeOH) in hexanes) to give(S)-tert-butyl2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(0.305g, 67%). LCMS-ESI⁺: calc'd for C₄₄H₄₉N₇O₅: 755.38 (M⁺). Found:756.8 (M+H⁺).

Methyl{(1R)-2-[(2S)-2-{2′-[(1S,3S,4R)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

Hydrogen chloride in dioxane solution (4N, 1.51 mL, 6.05 mmol) was addedto a solution of (S)-tert-butyl 2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(0.305g, 0.403 mmol) in methylene chloride:methanol (4.0 mL: 0.80 mL).The suspension was allowed to stir at room temperature for two hours.Upon completion by LCMS, the reaction was concentrated to dryness andthe crude product (assumed 0.403 mmol) was suspended in methylenechloride (4 mL). (R)-2-(methoxycarbonylamino)-2-phenylacetic acid(0.093g, 0.484 mmol) and DIPEA (0.282 mL, 1.61 mmol) were added and theslurry was cooled to −40° C. with an external dry ice/acetonitrile bath.COMU (0.259g, 0.605 mmol) was added at −40° C. and the solution wasstirred at reduced temperature for one hour. Upon completion, the crudereaction was diluted with DMF and concentrated in vacuo. The crudeproduct was purified by reverse phase HPLC (Gilson, Gemini, 10-45%acetonitrile/water with 0.1% TFA modifier). Fractions containing productwere combined and concentrated until aqueous layer remained. Aqueoussodium bicarbonate was added to aqueous product mixture to obtain a pHof 7-8 (as measured by pH paper) and precipitation was observed. Theprecipitate was filtered and dried under vacuum for 18 hours to givemethyl {(1R)-2-[(2S)-2-{2′-[(1S,3S,4R)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[2.2.1]hept-3-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(0.180g, 53%) as a while solid. LCMS-ESI⁺: calc'd for C₄₉H₅₀N₈O₆: 846.39(M⁺). Found: 847.8 (M+H⁺).

Example LZ

5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1 (2H1)-one

To a stirred solution of 5-hydroxy-1-tetralone (2.0 g, 12.3 mmol) and1-bromo-2-(bromomethyl)-4-chlorobenzene (3.6 g, 12.7 mmol) indimethylformamide (125 mL) was added potassium carbonate (3.5 g, 25.1mmol). The reaction was stirred under argon for 1 hour then diluted withethyl acetate (1 L). The organics were washed three times with water andonce with brine. The organic layer was then dried with magnesiumsulfate, filtered and concentrated. To the resulting oil was addedmethanol (100 mL) and the suspension was agitated for thirty minutes.5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (4.25 g,94% yield) was isolated by filtration.

8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one

To a flask containing palladium(II) pivalate (68 mg, 0.22 mmol),tri(4-fluorophenyl)phosphine (70 mg, 0.22 mmol), pivalic acid (135 mg,1.3 mmol) and potassium carbonate (1.83 g, 13.1 mmol) was added asolution of5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (1.61 g,4.4 mmol) in dimethyacetamide (23 mL). The flask was evacuated andbackfilled with argon 5 times and then stirred under argon at 60° C. for24 hours. The reaction was poured directly onto a silica gel column andpurified by flash column chromatography (hexanes/DCM) to yield8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one (1.22 g, 97%yield) as an off-white solid.

2-bromo-8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one

To a mixture of 8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one(2.58 g, 9.1 mmol) in chloroform (9.1 mL) and ethyl acetate (9.1 mL) wasadded copper(II) bromide (4.65 g, 19.9 mmol). The reaction was heated to80° C. for 5 hours and then cooled to room temperature. The mixture wasdiluted with dichloromethane and washed twice with a 5:1 solution ofsaturated aqueous ammonium chloride and aqueous ammonium hydroxide(˜28%), and washed once with water. The organic layer was dried withmagnesium sulfate, filtered and concentrated. The crude material waspurified by flash column chromatography (hexanes/DCM) to yield2-bromo-8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one (2.45g, 75% yield).

(2S)-1-tert-butyl2-(8-chloro-1-oxo-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-2-yl)pyrrolidine-1,2-dicarboxylate

To a solution of2-bromo-8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-1-one (1.05g, 2.9 mmol) and Boc-Pro-OH (1.75 g, 8.1 mmol) in acetonitrile (9.0 mL)was added diisopropylethylamine (1.5 mL, 8.7 mmol). The solution wasstirred under argon at 50° C. for two hours. Extra Boc-Pro-OH (620 mg,2.9 mmol) and diisopropylethylamine (0.5 mL, 2.9 mmol) were added andthe reaction was stirred at 50° C. for 16 hours. The reaction was cooledto room temperature and diluted with ethyl acetate. The organics werewashed with water and brine, dried with magnesium sulfate andconcentrated. The crude material was purified by flash columnchromatography and the product (2S)-1-tert-butyl2-(8-chloro-1-oxo-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-2-yl)pyrrolidine-1,2-dicarboxylate was isolated as a mixture of diastereomers(0.99 g, 69% yield).

tert-butyl(2S)-2-(9-chloro-3,4,5,7-tetrahydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of (2S)-1-tert-butyl2-(8-chloro-1-oxo-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-2-yl)pyrrolidine-1,2-dicarboxylate (2.2 g, 4.4 mmol) in toluene (40 mL) wasadded ammonium acetate (7 g, 91 mmol). The reaction mixture wasvigorously refluxed for 3 hours, then cooled to room temperature anddiluted with ethyl acetate. The organics were washed with water andbrine, dried with magnesium sulfate and concentrated. The crude materialwas purified by flash column chromatography to yield tert-butyl (2S)-2-(9-chloro-3,4,5,7-tetrahydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.13 g, 54% yield) as well as recovered (2S)-1-tert-butyl2-(8-chloro-1-oxo-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen-2-yl)pyrrolidine-1,2-dicarboxylate (0.8 g, 36%). LCMS-ESI⁺: calculated forC₂₇H₂₈N₃O₃: 477.98. observed [M+1]⁺: 478.54.

tert-butyl(2S)-2-(9-chloro-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of Intermediate tert-butyl(2S)-2-(9-chloro-3,4,5,7-tetrahydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.43 g, 3.0 mmol) in dichloromethane (30 mL) was added manganese(IV)oxide (15 g, 198 mmol). The mixture was stirred for four hours at roomtemperature then filtered through Celite. The MnO₂ was thoroughly rinsedwith dichloromethane and the total filtrate was concentrated to yieldtert-butyl(2S)-2-(9-chloro-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.37 g, 96% yield). This material was used without furtherpurification.

tert-butyl(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

To a solution of tert-butyl(2S)-2-(9-chloro-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.4 g, 2.9 mmol) in dioxane (20 mL) was added bis(pinacolato)diboron(1.5 g, 5.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (110 mg,0.12 mmol), X-Phos (145 mg, 0.30 mmol) and potassium acetate (870 mg,8.9 mmol). The mixture was degassed with a stream of argon for tenminutes. The degassed reaction was heated under argon to 90° C. for 2.5hours then cooled to room temperature and diluted with ethyl acetate.The organics were washed with water and brine, dried with magnesiumsulfate and concentrated. The crude material was purified by flashcolumn chromatography (DCM/EtOAc) to yield tert-butyl(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(1.5 g, 90% yield).

methyl[(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate

A solution of tert-butyl(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(0.98 g, 1.7 mmol), concentrated HCl (2 mL) and ethanol (20 mL) washeated to 60° C. for 2 hours. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offtwo more times. The resulting crude material was dissolved indimethylformamide (17 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (455 mg, 2.6 mmol),HATU (955 mg, 2.5 mmol) and diisopropylethylamine (3 mL, 17 mmol). Thereaction was stirred at room temperature for one hour then diluted withethyl acetate. The organics were washed with water (×2) and brine, driedwith magnesium sulfate and concentrated. The resulting residue waspurified by flash column chromatography to yield Intermediate methyl[(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate(780 mg, 72% yield over 2 steps).

tert-butyl(2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

A mixture of Pentacyclic Intermediate methyl[(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate(780 mg, 1.3 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (450 mg, 1.4mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol),PdCl₂(dppf) (60 mg, 0.08 mmol), 2M aqueous potassium carbonate (1.9 mL,3.9 mmol), dimethoxyethane (10 mL) and dimethylformamide (2 mL) wasdegassed with argon for 15 minutes. The reaction was then heated to 85°C. for 3 hours. Upon completion, the reaction was cooled to roomtemperature, diluted with ethyl acetate and filtered through Celite. Thefiltrate was washed with water and brine, dried (MgSO₄) andconcentrated. The resulting crude material was purified by flash columnchromatography (EtOAc/MeOH) to yield Intermediate tert-butyl(2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(390 mg, 43% yield).

methyl{(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A mixture of Intermediate tert-butyl(2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(390 mg, 0.53 mmol), concentrated HCl (2 mL) and ethanol (10 mL) washeated to 60° C. for 2 hours. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offtwo more times. One half of the crude material (˜0.27 mmol) wasdissolved in dimethylformamide (2.5 mL). To this solution was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (66 mg, 0.38 mmol),HATU (140 mg, 0.37 mmol) and diisopropylethylamine (0.48 mL, 2.7 mmol).The reaction was stirred at room temperature for 2 hours, and thendiluted with acetonitrile (2 mL) and methanol (2 mL). To this solutionwas added ten drops of 5M aqueous NaOH solution and stirring wascontinued for 30 minutes. The reaction was diluted with ethyl acetateand the organic layer was washed with water and brine. The combinedaqueous washings were extracted three times with ethyl acetate, and thecombined organic layers were dried (MgSO₄) and concentrated. The crudematerial was purified by reverse phase HPLC (Gemini, 15 to 45%ACN/H₂O+0.1% TFA) to yield methyl{(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(140 mg, 67% yield over 2 steps). LCMS-ESI⁺: calculated for C₄₃H₅₀N₈O₇:790.91. observed [M+1]⁺: 791.71.

Example MA

methyl{(1R)-2-[(2R)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

This compound was made in an analogous manner to Example methyl{(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate,substituting (R)-2-(methoxycarbonylamino)-2-phenylacetic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid and substituting COMUfor HATU in the final amide coupling step. LCMS-ESI⁺: calculated forC₄₆H₄₈N₈O₇: 824.92. observed [M+1]⁺: 825.72.

Example MB

tert-butyl(2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

A mixture of tert-butyl(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(450 mg, 0.79 mmol), methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(325 mg, 0.87 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg,0.02 mmol), PdCl₂(dppf) (35 mg, 0.05 mmol), 2M aqueous potassiumcarbonate (1.2 mL, 2.4 mmol), dimethoxyethane (6.8 mL) anddimethylformamide (1.2 mL) was degassed with argon for 15 minutes. Thereaction was then heated to 85° C. for 2.5 hours. Upon completion, thereaction was cooled to room temperature, diluted with ethyl acetate andfiltered through Celite. The filtrate was washed with water and brine,dried (MgSO₄) and concentrated. The resulting crude material waspurified by flash column chromatography (EtOAc/MeOH) to yield tert-butyl(2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate (270 mg, 46%yield).

methyl{(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A mixture of tert-butyl(2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(270 mg, 0.37 mmol), concentrated HCl (1.5 mL) and ethanol (8 mL) washeated to 60° C. for 1 hour. The reaction was concentrated andredissolved in a minimal amount of methanol. An equal volume ofdichloromethane was added and the solution was again concentrated.Dichloromethane was added to the resulting residue and concentrated offtwo more times. The crude material was dissolved in 5:1dichloromethane/dimethylformamide (3.8 mL). To this solution was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (96 mg, 0.46 mmol),COMU (190 mg, 0.44 mmol) and diisopropylethylamine (0.20 mL, 1.1 mmol).The reaction was stirred at 0° C. for 30 minutes then warmed to roomtemperature. Upon completion, the reaction was diluted with acetonitrile(2 mL) and methanol (2 mL). To this solution was added ten drops of 5Maqueous NaOH solution and stirring was continued for 30 minutes. Thereaction was diluted with ethyl acetate and the organic layer was washedwith water and brine. The combined aqueous washings were extracted threetimes with ethyl acetate, and the combined organic layers were dried(MgSO₄) and concentrated. The crude material was purified by reversephase HPLC (Gemini, 15 to 45% ACN/H₂O+0.1% TFA) to yield methyl{(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(155 mg, 51% yield over 2 steps). LCMS-ESI⁺: calculated for C₄₆H₄₈N₈O₇:824.92. observed [M+1]⁺: 825.67.

Example MC

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′1-pyrrolidin-2-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

This compound was made in an analogous manner to methyl{(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate,substituting 7-hydroxy-1-tetralone for 5-hydroxy-1-tetralone in thefirst step of the sequence. All reactions in the synthesis of Example MCgave similar product yields as in the synthesis of methyl{(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate.LCMS-ESI⁺: calculated for C₄₃H₅₀N₈O₇: 790.91; observed [M+1]⁺: 791.6.

Example MD

methyl[1-(2-{5-[2-(1-{[methoxycarbonyl)amino]-3-methyl-1-oxobutan-2-yl}pyrrolidin-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl)-phenyl-1-oxoacet-2-yl]carbamateExample MD

This compound was made in an analogous manner to dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′1-pyrrolidin-2-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate,substituting (R)-2-(methoxycarbonylamino)-2-phenylacetic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid and substituting COMUfor HATU in the final amide coupling step. LCMS-ESI⁺: calculated forC₄₆H₄₈N₈O₇: 824.92. observed [M+1]⁺: 825.67.

Example ME

dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′1-pyrrolidin-2-yl)-7H-dihydro-naphtho[c,g]chromeno[8,9-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

This compound was made in an analogous manner to dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′1-pyrrolidin-2-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate,omitting the MnO₂ oxidation of tert-butyl2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate.LCMS-ESI⁺: calculated for C₄₃H₅₂N₈O₇: 792.40. observed [M+1]⁺: 793.69.

Example MF

methyl[1-(2-{5-[2-(1-{[(methoxycarbonyl)amino]-3-methyl-1-oxobutan-2-yl}pyrrolidin-2-yl)-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl)-phenyl-1-oxoacet-2-yl]carbamate

methyl[1-(2-{5-[2-(1-{[(methoxycarbonyl)amino]-3-methyl-1-oxobutan-2-yl}pyrrolidin-2-yl)-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl]-1H-imidazol-2-yl}pyrrolidin-1-yl)-phenyl-1-oxoacet-2-yl]carbamate:This compound was made in an analogous manner to dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′1-pyrrolidin-2-yl)-7H-dihydro-naphtho[c,g]chromeno[8,9-d]imidazol-9-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate,substituting (R)-2-(methoxycarbonylamino)-2-phenylacetic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid and substituting COMUfor HATU in the final amide coupling step. LCMS-ESI⁺: calculated forC₄₆H₅₀N₈O₇: 826.94; observed [M+1]⁺: 827.71.

Example MG

Example MG

This compound was made in an analogous manner to methyl{(2S)-1-[(2R)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate,substituting tert-butyl (2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylatefor tert-butyl(2S)-2-[9-(2-{(2R)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate.LCMS-ESI⁺: calculated for C₄₆H₅₀N₈O₇: 826.94. observed [M+1]⁺: 827.64.

Example MH

6-bromo-2-methoxy-1-nitronaphthalene

2-Bromo-6-methoxynaphthalene (20 g, 84.4 mmol) was dissolved in aceticacid (140 mL) by stirring vigorously at 70° C. This solution was cooledto 50° C. and a solution of nitric acid (>90%, 4 mL) in acetic acid (28mL) was added dropwise. The resulting reaction mixture was stirred at50° C. for four hours and then cooled to room temperature. The yellowsolid was isolated by filtration and recrystallized from acetic acid toyield 6-bromo-2-methoxy-1-nitronaphthalene (18.7 g, 76% yield).

2-amino-6-bromo-1-nitronaphthalene

6-bromo-2-methoxy-1-nitronaphthalene (12.6 g, 44.7 mmol),dimethylformamide (25.6 mL) and 7N NH₃ solution in MeOH (128 mL,purchased from Sigma Aldrich) were combined in a Parr bomb. The bomb washeated in a lab oven at 130° C. After 48 hours, the reactor was removedfrom the oven and cooled to room temperature. The contents of the bombwere transferred to a glass round bottom flask. The bomb was thoroughlyrinsed with dichloromethane and methanol, and the rinsings added to theflask. The contents of the flask were thoroughly concentrated on arotary evaporator, leaving a brown solid. Water (200 mL) was added tothe flask and the resulting suspension was agitated with a stir bar for30 minutes. The resulting light brown powder was isolated by filtration,rinsing a few times with water. The filter cake was air dried over nightto yield 6-bromo-1-nitronaphthalen-2-amine (11.6 g, >95% yield).

6-bromonaphthalene-1,2-diamine

To a mixture of 6-bromo-1-nitronaphthalen-2-amine (11.6 g, 43.4 mmol) inethanol (430 mL) under argon was added Raney Nickel (˜5 g, NOTE: noeffort was made to remove the water from the nickel). Hydrogen gas wasbubbled through the reaction mixture for 2 minutes. The reaction wasstirred under an atmosphere of hydrogen at room temperature. After 16hours, the Raney Nickel was removed by filtration over Celite and rinsedwith ethyl acetate. The filtrate was thoroughly concentrated to yield6-bromonaphthalene-1,2-diamine (9.2 g, 88% yield).

Example MI

(S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

6-bromonaphthalene-1,2-diamine (1.92 g, 7.19 mmol),(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.55 g, 7.19mmol) and HATU (2.73 g, 7.19 mmol) were combined in DMF (18 mL). Thestirred mixture was cooled to 0° C. before DIPEA (2.5 mL, 14.4 mmol) wasadded dropwise. After 3 h, the reaction mixture was diluted with EtOAc(200 mL) and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (50% to 85% EtOAc/hexanes) to afford the amide adduct(regiochemistry undetermined, 2.71 g, 87%). The amide was dissolved inAcOH (50 mL) and heated to 40° C. for 18 h. After cooling to RT, thesolution was concentrated under reduced pressure. The crude residue wasdissolved in EtOAc (200 mL) and washed successively with saturatedaqueous NaHCO₃ (2×) and brine. The organics were dried over MgSO4,filtered and concentrated under reduced pressure to afford(S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(2.57 g, 99%).

Methyl(S)-1-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(1.50 g, 3.60 mmol) was dissolved in DCM (25 mL) and HCl (4 M solutionin dioxane, 5 mL, 20 mmol) was added at once. After stirring for 3 h,the solution was concentrated under reduced pressure. The crude residuewas treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (631mg, 3.60 mmol), HATU (1.37 g, 3.60 mmol) and DMF (18 mL). The stirredsolution was cooled to 0° C. and DIPEA (1.9 mL, 10 mmol) was addeddropwise. After stirring for 20 min, the reaction mixture was warmed toRT. After an additional 10 min, it was diluted with EtOAc (150 mL) andwashed successively with saturated aqueous NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(0% to 33% MeOH/EtOAc) to afford the title compound (1.70 g, 100%).

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

Methyl(S)-1-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(827 mg, 1.75 mmol), bis(pinacolato)diboron (532 mg, 2.10 mmol), KOAc(515 mg, 5.25 mmol) and Pd(dppf)Cl₂ (128 mg, 0.175 mmol) were combinedin dioxane (18 mL). The reaction mixture was degassed with bubbling N₂for 10 min, then stirred at 90° C. for 1.5 h. It was then cooled to RT,diluted with EtOAc (150 mL) and washed successively with saturatedaqueous NaHCO₃ and brine. The organics were dried over MgSO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedby silica column chromatography to afford methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(695 mg, 76%).

Example MJ

(2S,4R)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylateand (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

6-bromonaphthalene-1,2-diamine (837 mg, 3.53 mmol),(2S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (929 mg, 3.58 mmol) and HATU (1.34 g, 3.53 mmol) were combined inDMF (18 mL). The stirred mixture was cooled to 0° C. before DIPEA (1.5mL, 8.83 mmol) was added and the reaction was warmed to RT. After 18 h,the reaction mixture was diluted with EtOAc (200 mL) and washedsuccessively with saturated aqueous NaHCO₃ and brine. The organics weredried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (65% to 90%EtOAc/hexanes) to afford the amide adduct (regiochemistry undetermined,1.48 g, 87%). The amide was dissolved in AcOH (50 mL) and heated to 40°C. for 10 h. After cooling to RT, the solution was concentrated underreduced pressure. The crude residue was dissolved in EtOAc (200 mL) andwashed successively with saturated aqueous NaHCO₃ (2×) and brine. Theorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(50% to 75% EtOAc/hexanes) to afford (2S,4R)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(less polar product, 641 mg, 45%) and (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(more polar product, 582 mg, 41%).

Example MK

Methyl(S)-1-((2S,4S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(526 mg, 1.14 mmol) was dissolved in DCM (15 mL) and HCl (4 M indioxane, 3 mL, 12 mmol) was added. The reaction mixture was stirred for2 h and then concentrated under reduced pressure. The crude residue wastreated with (methoxycarbonylamino)-3-methylbutanoic acid (220 mg, 1.25mmol), HATU (433 mg, 1.14 mmol) and DMF (11 mL), then cooled to 0° C.DIPEA (0.99 mL, 5.7 mmol) was added dropwise and the reaction mixturewas immediately warmed to RT. After 45 min at RT, the mixture wasdiluted with EtOAc (100 mL) and washed successively with saturatedaqueous NaHCO₃, water and brine. The organics were dried over MgSO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (0% to 33% MeOH/EtOAc) toafford methyl(S)-1-((2S,4S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(584 mg, 99%).

Methyl{(2S)-1-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Methyl(S)-1-((2S,4S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(210 mg, 0.406 mmol), methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(253 mg, 0.487 mmol), Pd(PPh3)₄ (47 mg, 0.0406 mmol) and K₂CO₃ (2M inH₂O, 0.50 mL, 1.0 mmoL) were combined in DME (4 mL). The mixture wasdegassed with bubbling N₂ for 10 min the heated to 85° C. for 15 h.After cooling, the reaction mixture was diluted with 5 mL MeOH, filteredand concentrated. The crude residue was purified by reverse phase HPLCto afford methyl{(2S)-1-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(140 mg, 42%). MS (ESI) m/z 831 [M+H]⁺.

Example ML

(2S,4S)-tert-butyl2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(260 mg, 0.524 mmol), (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(201 mg, 0.437 mmol), Pd(PPh₃)₄ (50 mg, 0.0437 mmol) and K₂CO₃ (2 M inH₂O, 0.55 mL, 1.1 mmol) were combined in DME (4 mL). The reactionmixture was degassed with bubbling N₂, then heated to 85° C. for 5 h.Upon completion, the reaction mixture was cooled to RT, diluted with 5mL MeOH, filtered and concentrated. The crude residue was purified bysilica column chromatography (0% to 45% MeOH/EtOAc) to afford(2S,4S)-tert-butyl2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(163 mg, 50%).

Methyl{(1R)-2-[(2S,4S)-2-[7-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1H-naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

(2S,4S)-tert-butyl2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(140 mg, 0.187 mmol) was dissolved in DCM (5 mL) and HCl (4 M indioxane, 1 mL, 4 mmol) was added. After stirring for 1.5 h, the reactionmixture was concentrated under reduced pressure. The crude residue wastreated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (43 mg,0.206 mmol), COMU (80 mg, 0.187 mmol), DMF (3 mL) and DIPEA (0.33 mL,1.9 mmol). After stirring at RT for 20 min, the solution was dilutedwith 30 mL 10% MeOH/EtOAc. The organic layer was washed successivelywith saturated aqueous NaHCO₃ and brine. The organics were dried overMgSO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by silica column chromatography to afford methyl{(1R)-2-[(2S,4S)-2-[7-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1H-naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(106 mg, 68%). MS (ESI) m/z 841 [M+H]⁺.

Example MM

(2S,4S)-methyll{4-(methoxymethyl)-2-[(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A solution of (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(424 mg, 0.69 mmol), ethanol (6 mL) and concentrated HCl (2 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (10 mL). This solution was concentrated and tothis material was added a solution of2-methoxycarbonylamino-3-methylbutyric acid (152 mg, 0.86 mmol) and HATU(303 mg, 0.79 mmol) in DMF (6 mL). To the resulting solution was addeddiisopropylethylamine (360 μL, 2.08 mmol). After stirring for 2 hours atroom temperature, the reaction was diluted with ethyl acetate, washedwith 5% NaHCO₃ solution, water and brine, dried (Na₂SO₄), concentratedand dried under vacuum to give (2S,4S)-methyll{4-(methoxymethyl)-2-[(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate.

tert-butyl(2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

To a solution of(2S,4S)-methyll{4-(methoxymethyl)-2-[(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.69 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (220 mg, 0.69mmol), tetrakis(triphenylphosphine) palladium(0) (24 mg, 0.02 mmol) anddichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) (31 mg,0.04 mmol) in a mixture of 1,2-dimethoxyethane (6.0 mL) anddimethylformamide (1.0 mL) was added a solution of potassium carbonate(2M in water, 1.04 mL, 2.0 mmol). The resulting mixture was degassed andthen heated to 85° C. under argon for 18 hours. After cooling to roomtemperature, the reaction was diluted with ethyl acetate. The organicswere washed with water and brine, dried (Na₂SO₄), and concentrated. Thecrude residue was purified by flash chromatography to yield (tert-butyl(2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(145 mg, 27%).

methyl{(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A solution of tert-butyl(2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(145 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (51 mg, 0.24 mmol) andCOMU (92 mg, 021 mmol) in DMF (3 mL). To the resulting solution wasadded diisopropylethylamine (100 μL, 0.56 mmol). After stirring for 2hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 43% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give methyl{(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(68 mg, 39%). MS (ESI) m/z 870 [M+H]⁺. 1H NMR (400 MHz, dmso) δ 8.71 (s,1H), 8.22 (d, 1H, J=8 Hz), 8.09 (m, 1H), 7.88-7.63 (m, 6H), 7.36-7.29(m, 6H), 5.41 (d, 1H, J=8.4 Hz), 5.30-5.24 (m, 2H), 5.14-5.10 (m, 1H),4.13-3.09 (m, 15H), 2.47-1.80 (m, 8H), 0.80 (dd, 6H, J=6.4 Hz, J=23 Hz).

Example MN

tert-butyl(2S,4S)-2-[9-(2-{(2S4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(438 mg, 0.72 mmol), methyl(S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(276 mg, 0.72 mmol), tetrakis(triphenylphosphine) palladium(0) (41 mg,0.04 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (52 mg, 0.07 mmol) in a mixture of1,2-dimethoxyethane (8.6 mL) and dimethylformamide (1.5 mL) was added asolution of potassium carbonate (2M in water, 1.07 mL, 2.15 mmol). Theresulting mixture was degassed and then heated to 85° C. under argon for18 hours. After cooling to room temperature, the reaction was dilutedwith ethyl acetate. The organics were washed with water and brine, dried(Na₂SO₄), and concentrated. The crude residue was purified by flashchromatography to yield tert-butyl(2S,4S)-2-[9-(2-{(2S4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(182 mg, 32%).

methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A solution of tert-butyl(2S,4S)-2-[9-(2-{(2S4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (182 mg, 0.18 mmol), ethanol (3 mL) andconcentrated HCl (1 mL) was heated to 60° C. for 1 hour. The reactionwas concentrated and the crude material dissolved in DCM (6 mL). Thissolution was concentrated and to this material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (47 mg, 0.23 mmol) andCOMU (85 mg, 0.2 mmol) in DMF (3 mL). To the resulting solution wasadded diisopropylethylamine (90 μL, 0.52 mmol). After stirring for 2hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 49% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to givemethyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(32 mg, 39%). MS (ESI) m/z 884 [M+H]⁺.

1H NMR (400 MHz, dmso) δ 8.70 (s, 1H), 8.21 (d, 1H, J=8 Hz), 8.08 (s,1H), 7.90-7.64 (m, 6H), 7.34-7.31 (m, 3H), 7.64 (d, 1H, J=8.4 Hz), 5.47(d, 1H, J=7.6 Hz), 5.28-5.25 (m, 3H), 5.05-5.01 (m, 1H), 4.19-4.04 (m,3H), 3.67-3.15 (m, 15H), 2.51-2.46 (m, 4H), 1.95-1.92 (m, 2H), 1.82-1.76(m, 1H), 1.10 (d, 3H, J=6 Hz), 0.75 (dd, 6H, J=6.8 Hz, J=14 Hz).

Example MO

methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methoxymethylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To a solution of methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidi-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(57 mg, 0.08 mmol), 2-methoxycarbonylamino-3-methylbutyric acid (19 mg,0.1 mmol), HATU (303 mg, 0.79 mmol) in DMF (1 mL) was addeddiisopropylethylamine (43 μL, 0.24 mmol). After stirring for 2 hours atroom temperature, the reaction was diluted with ethyl acetate, washedwith 5% NaHCO₃ solution, water and brine, dried (Na₂SO₄), concentratedand purified by preparative reverse phase HPLC (Gemini, 15 to 43%ACN/H₂O+0.1% TFA). The product fractions were lyophilized to give methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methoxymethylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate.(13 mg, 19%). MS (ESI) m/z 850 [M+H]⁺.

1H NMR (400 MHz, dmso) δ 8.66 (s, 1H), 8.28-8.13 (m, 1H), 8.12-7.99 (m,1H), 7.90-7.75 (m, 3H), 7.73-7.65 (m, 1H), 7.63-7.57 (m, 1H), 7.34-7.19(m, 2H), 5.30-5.24 (m, 2H), 5.21-4.95 (m, 2H), 4.33-3.93 (m, 6H),3.23-3.58 (m, 12H), 2.76-2.59 (m, 2H), 2.02-1.73 (m, 6H), 1.12-1.07 (m,3H), 0.86-0.68 (m, 12H).

Example MP

tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(217 mg, 0.35 mmol), methyl(S)-1-((2S,5S)-2-(5-bromo-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(170 mg, 0.39 mmol), tetrakis(triphenylphosphine) palladium(0) (21 mg,0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (26 mg, 0.04 mmol) in a mixture of1,2-dimethoxyethane (4.3 mL) and dimethylformamide (0.75 mL) was added asolution of potassium carbonate (2M in water, 0.53 mL, 1.06 mmol). Theresulting mixture was degassed and then heated to 85° C. under argon for18 hours. After cooling to room temperature, the reaction was dilutedwith ethyl acetate. The organics were washed with water and brine, dried(Na₂SO₄), and concentrated. The crude residue was purified by flashchromatography to yield tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (110 mg, 39%).

methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methoxymethylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A solution of tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (108 mg, 0.14 mmol), ethanol (2 mL) andconcentrated HCl (0.7 mL) was heated to 60° C. for 1 hour. The reactionwas concentrated and the crude material dissolved in DCM (10 mL). Thissolution was concentrated and to this material was added a solution of2-methoxycarbonylamino-3-methylbutyric acid (31 mg, 0.18 mmol) and HATU(60 mg, 0.16 mmol) in DMF (2 mL). To the resulting solution was addeddiisopropylethylamine (70 μL, 0.41 mmol). After stirring for 2 hours atroom temperature, the reaction was diluted with ethyl acetate, washedwith 5% NaHCO₃ solution, water and brine, dried (Na₂SO₄), After stirringfor 2 hours at room temperature, the reaction was diluted with ethylacetate, washed with 5% NaHCO₃ solution, water and brine, dried(Na₂SO₄), concentrated and purified by preparative reverse phase HPLC(Gemini, 15 to 43% ACN/H₂O+0.1% TFA). The product fractions werelyophilized to give methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methoxymethylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(52 mg, 45%). MS (ESI) m/z 850 [M+H]⁺.

1H NMR (400 MHz, dmso) δ 8.69 (s, 1H), 8.18 (d, 1H, J=7.6 Hz), 7.99-7.86(m, 4H), 7.72 (s, 111), 7.64 (d, 1H, J=8.8 Hz), 7.51 (d, 1H, J=8 Hz),7.23 (d, 1H, J=8.4 Hz), 5.29 (s, 2H), 5.22-5.18 (m, 1H), 5.01-4.70 (m,1H), 4.64-4.61 (m, 1H), 4.21-4.17 (m, 1H), 4.09-4.05 (m, 1H), 3.92-3.88(m, 1H), 3.59-3.08 (m, 14H), 2.67-1.83 (m, 7H), 1.43 (d, 3H, J=6.4 Hz),0.91-0.71 (m, 12H).

Example MQ

(2S,4R)-tert-butyl-4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

A degassed mixture of-(2S,4R)-tert-butyl-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (335 mg, 0.64 mmol), bis(pinacolato)diboron(246 mg, 0.96 mmol), potassium acetate (190 mg, 1.9 mmol),tris(dibenzylideneacetone) palladium (24 mg, 0.02 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (31 mg, 0.06mmol) in 1,4-dioxane (3.3 mL) was heated to 90° C. for 3 hours, cooledto room temperature and diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield (2S,4R)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(379 mg, 96%).

(2S,4R)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (2S,4R)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (299 mg, 0.49 mmol), methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(217 mg, 0.58 mmol), tetrakis(triphenylphosphine) palladium(0) (28 mg,0.02 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (35 mg, 0.04mmol) in a mixture of 1,2-dimethoxyethane (4.3 mL) and dimethylformamide(0.75 mL) was added a solution of potassium carbonate (2M in water, 0.73mL, 1.46 mmol). The resulting mixture was degassed and then heated to85° C. under argon for 18 hours. After cooling to room temperature, thereaction was diluted with ethyl acetate. The organics were washed withwater and brine, dried (Na₂SO₄), and concentrated. The crude residue waspurified by flash chromatography to yield (2S,4R)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(170 mg, 45%).

methyl{(1R)-2-[(2S,4R)-2-(9-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-phenylethyl}carbamate

A solution of (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (170 mg, 0.22 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and tothis material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (59 mg, 0.28 mmol) andCOMU (108 mg, 025 mmol) in DMF (3 mL). To the resulting solution wasadded diisopropylethylamine (110 μL, 0.66 mmol). After stirring for 2hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give methyl{(1R)-2-[(2S,4R)-2-(9-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]-naphtho[1,2-d]imidazol-2-yl}-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-phenylethyl}carbamate (67 mg, 35%). MS (ESI) m/z870 [M+H]⁺. 1H NMR (400 MHz, dmso) δ 8.71 (s, 11H), 8.20 (d, 1H, J=8.4Hz), 8.01 (m, 1H), 7.91-7.64 (m, 6H), 7.38-7.28 (m, 6H), 6.85 (s, 1H),5.51 (d, 1H, J=7.2 Hz), 5.39-5.29 (m, 3H), 5.13-5.09 (m, 1H), 4.11-3.04(m, 15H), 2.77-1.98 (m, 8H), 0.79 (dd, 6H, J=6.8 Hz, J=12.8 Hz).

Example MR

(2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

A degassed mixture of (2S,4S)-tert-butyl2-(9-chloro-4,5-dihydro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(322 mg, 0.61 mmol), bis(pinacolato)diboron (235 mg, 0.92 mmol),potassium acetate (182 mg, 1.9 mmol),tris(dibenzylideneacetone)palladium (23 mg, 0.02 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (29 mg, 0.06mmol) in 1,4-dioxane (3.3 mL) was heated to 90° C. for 3 hours, cooledto room temperature and diluted with ethyl acetate. The organics werewashed with water and brine, dried (Na₂SO₄), and concentrated. The cruderesidue was purified by flash chromatography to yield (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(267 mg, 70%).

(2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl-4,5-dihydro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(267 mg, 0.52 mmol), methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(195 mg, 0.52 mmol), tetrakis (triphenylphosphine) palladium(0) (25 mg,0.02 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (32 mg, 0.04mmol) in a mixture of 1,2-dimethoxyethane (4.3 mL) and dimethylformamide(0.75 mL) was added a solution of potassium carbonate (2M in water, 0.65mL, 1.3 mmol). The resulting mixture was degassed and then heated to 85°C. under argon for 18 hours. After cooling to room temperature, thereaction was diluted with ethyl acetate. The organics were washed withwater and brine, dried (Na₂SO₄), and concentrated. The crude residue waspurified by flash chromatography to yield (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl-4,5-dihydro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (75 mg, 22%).

methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]-4,5-dihydro-naphtho[1,2-d]imidazol-2-yl}-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl-4,5-dihydro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (75 mg, 0.09 mmol), ethanol (2 mL) andconcentrated HCl (0.6 mL) was heated to 60° C. for 1 hour. The reactionwas concentrated and the crude material dissolved in DCM (6 mL). Thissolution was concentrated and to this material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (26 mg, 0.13 mmol) andCOMU (47 mg, 0.11 mmol) in DMF (2 mL). To the resulting solution wasadded diisopropylethylamine (50 μL, 0.29 mmol). After stirring for 2hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]-4,5-dihydro-naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(15 mg, 18%).

MS (ESI) m/z 872 [M+H]⁺.

1H NMR (400 MHz, dmso) δ 7.95-7.63 (m, 6H), 7.35-7.25 (m, 7H), 6.97 (s,1H), 5.42 (d, 1H, J=6.8 Hz), 5.18 (s, 2H), 5.09 (s, 2H), 4.28-2.63 (m,19H), 2.47-1.80 (m, 8H), 0.77 (dd, 6H, J=4.8 Hz, J=12.4 Hz).

Example MS

(2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (2S,4S)-tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(400 mg, 0.85 mmol), methyl(S)-1-((S)-2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(360 mg, 0.85 mmol), tetrakis(triphenylphosphine) palladium(0) (38 mg,0.03 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (48 mg, 0.07 mmol) in a mixture of1,2-dimethoxyethane (8.0 mL) and dimethylformamide (1.4 mL) was added asolution of potassium carbonate (2M in water, 0.98 mL, 1.96 mmol). Theresulting mixture was degassed and then heated to 85° C. under argon for18 hours. After cooling to room temperature, the reaction was dilutedwith ethyl acetate. The organics were washed with water and brine, dried(Na₂SO₄), and concentrated. The crude residue was purified by flashchromatography to (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(156 mg, 29%).

methyl{(2S)-2-[[(2S,4S)-2-{9-[2-((2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl]-1,1-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A solution of (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(156 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and to(90 mg, 0.12 mmol) of this material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (34 mg, 0.16 mmol) andCOMU (61 mg, 014 mmol) in DMF (2 mL). To the resulting solution wasadded diisopropylethylamine (60 μL, 0.37 mmol). After stirring for 2hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 49% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give methyl{(2S)-2-[[(2S,4S)-2-{9-[2-((2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(62 mg, 56%). MS (ESI) m/z 920 [M+H]⁺.

1H NMR (400 MHz, dmso) δ 8.73 (s, 1H), 8.17 (d, 2H, J=8.4 Hz), 7.94 (d,3H, J=8.8 Hz), 7.84-7.67 (m, 6H), 7.37-7.29 (m, 6H), 5.48 (d, 1H, J=7.6Hz), 5.35-5.20 (m, 5H), 4.14-3.12 (m, 15H), 2.52-1.92 (m, 8H), 0.80 (dd,6H, J=6.8 Hz, J=6.4 Hz).

Example MT

methyl{(2S)-2-[(2S,4S)-2-{9-[2-((2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A solution of(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(156 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (6 mL). This solution was concentrated and to(68 mg, 0.09 mmol) of this material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (21 mg, 0.12 mmol) andCOMU (41 mg, 01 mmol) in DMF (1 mL). To the resulting solution was addeddiisopropylethylamine (50 μL, 0.28 mmol). After stirring for 2 hours atroom temperature, the reaction was diluted with ethyl acetate, washedwith water and brine, dried (Na₂SO₄), concentrated and purified bypreparative reverse phase HPLC (Gemini, 15 to 44% ACN/H₂O+0.1% TFA). Theproduct fractions were lyophilized to give methyl{(2S)-2-[(2S,4S)-2-{9-[2-((2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(32 mg, 40%). MS (ESI) m/z 886 [M+H]⁺.

1H NMR (400 MHz, dmso) δ 8.71 (s, 1H), 8.15 (d, 1H, J=8 Hz), 7.95-7.64(m, 8H), 7.28 (dd, 2H, J=8.8 Hz, J=14.4 Hz), 5.31 (s, 2H), 5.23-5.19 (m,2H), 4.09-3.85 (m, 5H), 3.58-3.28 (m, 14H), 2.47-1.89 (m, 9H), 0.83-0.72(m, 12H).

Example MU

tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of (2S)-methyll{-2-[(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1yl]-3-methyl-1-oxobutan-2-yl}carbamate(460 mg, 0.74 mmol), (2S,4S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(250 mg, 0.61 mmol), tetrakis (triphenylphosphine) palladium(0) (35 mg,0.03 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (45 mg, 0.06 mmol) in a mixture of1,2-dimethoxyethane (9.0 mL) and dimethylformamide (1.5 mL) was added asolution of potassium carbonate (2M in water, 0.92 mL, 1.84 mmol). Theresulting mixture was degassed and then heated to 85° C. under argon for18 hours. After cooling to room temperature, the reaction was dilutedwith ethyl acetate. The organics were washed with water and brine, dried(Na₂SO₄), and concentrated. The crude residue was purified by flashchromatography to tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(123 mg).

methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A solution tert-butyl (2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-carboxylate(122 mg, 0.16 mmol), ethanol (3 mL) and concentrated HCl (1 mL) washeated to 60° C. for 1 hour. The reaction was concentrated and the crudematerial dissolved in DCM (3 mL). This solution was concentrated and tothis material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (43 mg, 0.2 mmol) andCOMU (77 mg, 018 mmol) in DMF (3 mL). To the resulting solution wasadded diisopropylethylamine (80 μL, 0.37 mmol). After stirring for 2hours at room temperature, the reaction was diluted with ethyl acetate,washed with water and brine, dried (Na₂SO₄), concentrated and purifiedby preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H₂O+0.1% TFA).The product fractions were lyophilized to give methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(60 mg, 44%). MS (ESI) m/z 870 [M+H]⁺.

1H NMR (400 MHz, dmso) δ 8.71 (s, 1H), 8.22 (d, 1H, J=8 Hz), 8.09 (m,1H), 7.88-7.63 (m, 6H), 7.36-7.29 (m, 6H), 5.41 (d, 1H, J=8.4 Hz),5.30-5.24 (m, 2H), 5.14-5.10 (m, 1H), 4.13-3.09 (m, 15H), 2.47-1.80 (m,8H), 0.80 (dd, 6H, J=6.4 Hz, J=23 Hz).

Example MV

(1R,3S,5R)-tert-butyl3-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methoxymethylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo13.1.01 hexane-2-carboxylate

To a solution of (1R,3S,5R)-tert-butyl-3-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(213 mg, 0.37 mmol), methyl(S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(142 mg, 0.31 mmol), tetrakis (triphenylphosphine) palladium(0) (35 mg,0.03 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol) in a mixture of 1,4-dioxane(3.0 mL) and dimethylsulfoxide (3.0 mL) was added a solution ofpotassium carbonate (2M in water, 0.46 mL, 0.9 mmol). The resultingmixture was degassed and then heated to 95° C. under argon for 7 hours.After cooling to room temperature, the reaction was diluted with ethylacetate. The organics were washed with water and brine, dried (Na₂SO₄),and concentrated. The crude residue was purified by flash chromatographyto (1R,3S,5R)-tert-butyl 3-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methoxymethylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate(101 mg, 42%).

methyl{(1R)-2-[(1R,3S,5R)-2-(9-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methoxymethylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-azabicyclo[3.1.0]hex-3-yl]-2-oxo-1-phenylethyl}carbamate

A solution (1R,3S,5R)-tert-butyl3-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methoxymethylpyrrolidin-2-yl)-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (101 mg, 0.16 mmol), ethanol (3 mL)and concentrated HCl (1 mL) was heated to 60° C. for 1 hour. Thereaction was concentrated and the crude material dissolved in DCM (3mL). This solution was concentrated and to this material was added asolution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (35 mg,0.17 mmol) and COMU (63 mg, 015 mmol) in DMF (3 mL). To the resultingsolution was added diisopropylethylamine (70 μL, 0.38 mmol). Afterstirring for 2 hours at room temperature, the reaction was diluted withethyl acetate, washed with water and brine, dried (Na₂SO₄), concentratedand purified by preparative reverse phase HPLC (Gemini, 15 to 44%ACN/H₂O+0.1% TFA). The product fractions were lyophilized to give methylmethyl {(1R)-2-[(1R,3S,5R)-2-(9-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methoxymethylpyrrolidin-2-yl]-1H-imidazol-5yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-3-yl]-2-oxo-1-phenylethyl}carbamate(71 mg, 63).

MS (ESI) m/z 882 [M+H]⁺.

1H NMR (400 MHz, dmso) δ 8.66 (s, 1H), 8.17 (d, 1H, J=8.8 Hz), 8.04 (s,1H), 7.87-7.59 (m, 6H), 7.39-7.22 (m, 6H), 5.72 (d, 1H, J=7.6 Hz), 5.68(s, 1H), 5.25 (s, 1H), 5.13-5.01 (m, 2H), 4.12-4.00 (m, 2H), 3.81-3.00(m, 13H), 2.60 (m, 1H), 2.43-2.37 (m, 3H), 1.92-1.82 (m, 3H), 0.83-0.58(m, 7H), 0.59 (s, 1H), 0.00 (s, 1H).

Example MW

methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(1R,3S,5R)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-azabicyclo[3.1.0]hex-3-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(difluoromethoxy)methylpyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

This compound was synthesized using the same conditions as example 00substituting with the respective (1R,3S,5R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid and(2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylicacid as appropriate.

MS (ESI) m/z 918 [M+H]⁺.

Example MX

methyl {(1R)-2-[(2S,4S)-2-(9-{2-[(1R,3S,5R)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-5-azabicyclo[3.1.0]hex-3-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(difluoromethoxy)methylpyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

This compound was synthesized using the same conditions as example 00substituting with the respective(1R,3S,5R)-2-((2S,3S)-3-methoxy-2(methoxycarbonylamino)butanoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid and(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid as appropriate.

MS (ESI) m/z 898 [M+H]⁺.

Example MY

(2S,4S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-methylpyrrolidine-1,2-dicarboxylate

To a solution of9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.32 g,3.63 mmol) in MeCN (40 mL) was added(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(1.0 g, 4.36 mmol) and DIPEA (0.7 mL, 3.99 mmol). After stirring for 18h, the solution was diluted with EtOAc and washed successively withsaturated aqueous NaHCO₃ and brine. The organics were dried over MgSO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (10% to 40% EtOAc/hexanes) toafford (2S,4S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-methylpyrrolidine-1,2-dicarboxylate (1.31 g, 70%).

(2S,4S)-tert-butyl2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

(2S,4S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-methylpyrrolidine-1,2-dicarboxylate (1.31 g, 2.56 mmol) was addedxylenes (25 mL) and ammonium acetate (3.95 g, 51.2 mmol) and thesolution was heated to 136° C. and stirred overnight. The followingmorning, the solution was cooled to rt and was diluted with EtOAc andwashed successively with water, saturated aqueousNaHCO_(3 and brine. The organics were dried over MgSO) ₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (60% to 100% EtOAc/hexanes) to afford(2S,4S)-tert-butyl2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(711 mg, 56%).

(2S,4S)-tert-butyl2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

To a solution of (2S,4S)-tert-butyl2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methyl)pyrrolidine-1-carboxylate(935 mg, 1.9 mmol) in CH₂Cl₂ (20 mL) was added MnO₂ (8.25 g, 95 mmol).The reaction mixture was stirred for 3 h, and then filtered over celite.The filter cake was washed with copious CH₂Cl₂ and MeOH, and thefiltrate was concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (0% to 10% MeOH/EtOAc) toafford (2S,4S)-tert-butyl2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(692 mg, 74%).

(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

(2S,4S)-tert-butyl2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(692 mg, 1.41 mmol) in dioxane (15 mL) was added bis(pinacolato)diboron(1.07 g, 4.23 mmol), KOAc (415 mg, 4.23 mmol), X-Phos (52 mg, 0.11mmol), and Pd₂dba₃ (26 mg, 0.03 mmol). The solution was degassed with N₂for 10 min, then heated to 100° C. for 16 h. The solution was cooled tort, diluted with EtOAc, washed with saturated aqueous NaHCO₃, brine,dried with MgSO₄, and concentrated. Purified by silica gelchromatography (0% to 30% MeOH/EtOAc) to afford(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(821 mg, quant).

(2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4(methyl)pyrrolidine-1-carboxylate

To a solution of(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(821 mg, 1.41 mmol), methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(1.05 g, 2.82 mmol), tetrakis(triphenylphosphine) palladium(0) 162 mg,0.14 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (102 mg,0.14 mmol) in DME (15 mL) was added a solution of potassium carbonate(2M in water, 2.32 mL, 4.65 mmol). The resulting mixture was degassedand then heated to 85° C. for 18 hours. After cooling to roomtemperature, the reaction was diluted with ethyl acetate. The organicswere washed with saturated sodium bicarbonate and brine, dried overMgSO₄ and concentrated. The crude residue was purified by flashchromatography to yield (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4methylpyrrolidine-1-carboxylate(386 mg, 37%).

Methyl{2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A solution of (2S,4S)-tert-butyl2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4methylpyrrolidine-1-carboxylate(386 mg, 0.52 mmol), CH₂C2 (8 mL), MeOH (2 mL) and HCl (4M in Dioxane, 2mL) and was stirred overnight. The reaction was concentrated and thecrude material dissolved in DMF (8 mL). This solution was concentratedand to this material was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (108 mg, 0.52 mmol) andCOMU (248 mg, 0.52 mmol). To the resulting solution was addeddiisopropylethylamine (0.45 mL, 2.6 mmol). After stirring for 2 hours atroom temperature, the reaction was diluted with 10% MeOH/EtOAc, washedwith saturated NaHCO₃ water and brine, dried (Na₂SO₄), concentrated andpurified by HPLC to give methyl{2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-methylpyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(27 mg, 6%)_LCMS-ESI⁺: calculated for C₄₇H₅₀N₈O₇: 838.38. observed[M+1]⁺: 840.12.

Example MZ

(S)-2-(2-(4-bromo-3-iodophenyl)-2-oxoethyl) 1-tert-butylpyrrolidine-1,2-dicarboxylate

To a solution of 2-bromo-1-(4-bromo-3-iodophenyl)ethanone (20 mmol) inacetone (65 mL) was added(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (3, 14 mmol),K₂CO₃ (2.5 g, 18 mmol), and KI (235 mg, 1.4 mmol). After stirring for 15h, the solution was diluted with EtOAc and washed successively withsaturated aqueous NaHCO₃ and brine. The organics were dried over MgSO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography to afford(S)-2-(2-(4-bromo-3-iodophenyl)-2-oxoethyl) 1-tert-butylpyrrolidine-1,2-dicarboxylate (3.6 g, 34%).

(S)-tert-butyl2-(5-(4-bromo-3-iodophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To (S)-2-(2-(4-bromo-3-iodophenyl)-2-oxoethyl) 1-tert-butylpyrrolidine-1,2-dicarboxylate (3.6 g, 6.7 mmol) was added PhMe (65 mL)and ammonium acetate (5.5 g, 67 mmol) and the solution was heated to110° C. and stirred overnight. The following morning, the solution wascooled to rt and was diluted with EtOAc and washed successively withwater, saturated aqueous NaHCO₃ and brine. The organics were dried overMgSO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography (40% to 100%EtOAc/hexanes) to afford (S)-tert-butyl2-(5-(4-bromo-3-iodophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(2.9 g, 84%).

(S)-tert-butyl2-(5-(4-bromo-3-(prop-1-ynyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To (S)-tert-butyl2-(5-(4-bromo-3-iodophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.5 g, 2.9 mmol) was added PdCl₂(PPh₃)₄ (145 mg, 0.2 mmol), CuI (77 mg,0.4 mmol) and Et₃N (29 mL). Prop-1-yne was bubbled through the solutionand the reaction mixture was heated to 50° C. for 1.5 h. After cooling,the solution was diluted with EtOAc, washed with NH₄Cl, water, andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica gelchromatography to afford (S)-tert-butyl2-(5-(4-bromo-3-(prop-1-ynyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.25 g).

Methyl(S)-1-((S)-2-(5-(4-bromo-3-(prop-1-ynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-tert-butyl2-(5-(4-bromo-3-(prop-1-ynyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(400 mg, 0.98 mmol) was dissolved in DCM (8 mL), MeOH (2 mL) and HCl (4M in dioxane, 2 mL) was added. The reaction mixture was stirred for 22 hand then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (163 mg,0.93 mmol), HATU (354 mg, 0.98 mmol) and DMF (10 mL), then DIPEA (0.81mL, 4.65 mmol) was added dropwise. After 2 h, the mixture was dilutedwith EtOAc and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica gelchromatography (0% to 30% MeOH/EtOAc) to afford methyl(S)-1-((S)-2-(5-(4-bromo-3-(prop-1-ynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(369 mg, 81%).

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(3-(prop-1-ynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate

Methyl(S)-1-((S)-2-(5-(4-bromo-3-(prop-1-ynyl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(369 mg, 0.76 mmol) in dioxane (10 mL) was added bis(pinacolato)diboron(232 mg, 0.91 mmol), KOAc (223 mg, 2.28 mmol), and Pd(dppf)₂Cl₂ (56 mg,0.076 mmol). The solution was degassed with N₂ for 10 min, then heatedto 90° C. for 5 h. The solution was cooled to rt, diluted with EtOAc,washed with saturated aqueous NaHCO₃, brine, dried with MgSO₄, andconcentrated. Purified by silica gel chromatography (0% to 30%MeOH/EtOAc) to afford methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(3-(prop-1-ynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(153 mg, 38%).

(2S,4S)-tert-butyl2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-2-(prop-1-ynyl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

Methyl(S)-3-methyl-1-oxo-1-((S)-2-(5-(3-(prop-1-ynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate(153 mg, 0.28 mmol), (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(158 mg, 0.34 mmol), Pd(PPh3)₄ (32 mg, 0.028 mmol), Pd(dppf)₂Cl₂ (20 mg,0.028 mmol), and K₂CO₃ (2M in H₂O, 0.46 mL, 0.92 mmoL) were combined inDME (4 mL). The mixture was degassed with bubbling N₂ for 10 min theheated to 85° C. for 16 h. After cooling, the reaction mixture wasdiluted with EtOAc, and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (0% to % MeOH/EtOAc) to afford(2S,4S)-tert-butyl2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-2-(prop-1-ynyl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(66 mg, 30%).

Methyl(R)-2-((2S,4S)-2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-2-(prop-1-ynyl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

(2S,4S)-tert-butyl2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-2-(prop-1-ynyl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(66 mg, 0.084 mmol) was dissolved in DCM (2 mL), MeOH (0.5 mL) and HCl(4 M in dioxane, 0.5 mL) was added. The reaction mixture was stirred for2 h and then concentrated under reduced pressure. The crude residue wastreated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (18 mg,0.084 mmol), COMU (40 mg, 0.084 mmol) and DMF (3 mL), then DIPEA (0.73mL, 0.42 mmol) was added dropwise. After 15 h, the mixture was dilutedwith 10% MeOH/EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byHPLC to afford methyl(R)-2-((2S,4S)-2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-2-(prop-1-ynyl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(16 mg, 21%). LCMS-ESI⁺: calculated for C50H54N8O7: 878.41. observed[M+1]⁺: 879.60.

Example NA

(2S,4S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl4-methylpyrrolidine-1,2-dicarboxylate

To a solution of 2-bromo-1-(4-bromophenyl)ethanone (505 mg, 1.82 mmol)in MeCN (18 mL) was added(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(500 mg, 2.18 mmol) and triethyl amine (0.27 mL, 2.0 mmol). Afterstirring for 15 h, the solution was diluted with EtOAc and washedsuccessively with saturated aqueous NaHCO₃ and brine. The organics weredried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (10% to 35%EtOAc/hexanes) to afford (2S,4S)-2-(2-(4-bromophenyl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (748 mg, 97%).

(2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

(2S,4S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl4-methylpyrrolidine-1,2-dicarboxylate (748 mg, 1.75 mmol) was added PhMe(17 mL) and ammonium acetate (2.7 g, 35 mmol) and the solution washeated to 110° C. and stirred overnight. The following morning, thesolution was cooled to rt and was diluted with EtOAc and washedsuccessively with water, saturated aqueous NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(60% to 100% EtOAc/hexanes) to afford (2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(606 mg, 85%).

(2S,4S)-tert-butyl4-methyl-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(2S,4S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(606 mg, 1.49 mmol) in dioxane (15 mL) was added bis(pinacolato)diboron(455 mg, 1.79 mmol), KOAc (439 mg, 4.47 mmol), and Pd(dppf)₂Cl₂ (109 mg,0.15 mmol). The solution was degassed with N₂ for 10 min, then heated to90° C. for 2.5 h. The solution was cooled to rt, diluted with EtOAc,washed with saturated aqueous NaHCO₃, brine, dried with MgSO₄, andconcentrated. Purified by silica gel chromatography (0% to 30%MeOH/EtOAc) to afford (2S,4S)-tert-butyl4-methyl-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(628 mg, 93%).

(2S,4S)-tert-butyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

Methyl(S)-1-((2S,4S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(621 mg, 1.26 mmol), (2S,4S)-tert-butyl4-methyl-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(628 mg, 1.39 mmol), Pd(PPh₃)₄ (145 mg, 0.13 mmol), and K₂CO₃ (2M inH₂O, 2.0 mL, 4.16 mmoL) were combined in DME (13 mL). The mixture wasdegassed with bubbling N₂ for 10 min the heated to 85° C. for 16 h.After cooling, the reaction mixture was diluted with EtOAc, and washedsuccessively with saturated aqueous NaHCO₃ and brine. The organics weredried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (0% to 30%MeOH/EtOAc) to afford (2S,4S)-tert-butyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(342 mg, 37%).

Tert-butyl(R)-2-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

(2S,4S)-tert-butyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(342 mg, 0.46 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The crude residuewas treated with (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid(116 mg, 0.46 mmol), COMU (220 mg, 0.64 mmol) and DMF (5 mL), then DIPEA(0.4 mL, 2.31 mmol) was added dropwise. After 2 h, the mixture wasdiluted with EtOAc and washed successively with saturated aqueous NaHCO₃and brine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (0% to 30% MeOH/EtOAc) to afford tert-butyl(R)-2-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(296 mg, 74%).

Methyl(S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Tert-butyl(R)-2-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(296 mg, 0.33 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The crude residuewas treated with cyclopropanecarboxylic acid (38 μL, 0.28 mmol), COMU(162 mg, 0.34 mmol) and DMF (4 mL), then DIPEA (0.29 mL, 1.65 mmol) wasadded dropwise. After 30 min, the mixture was diluted with 10%MeOH/EtOAc and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by HPLC to affordmethyl(S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(68 mg, 24%). LCMS-ESI⁺: calculated for C48H56N8O6: 840.43. observed[M+1]⁺: 842.14.

Example NB

Methyl[(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate

(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-(methyl)pyrrolidine-1-carboxylate(950 mg, 1.63 mmol) was dissolved in DCM (12 mL), MeOH (3 mL) and HCl (4M in dioxane, 3 mL) was added. The reaction mixture was stirred for 4 hand then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (285 mg,1.63 mmol), HATU (620 mg, 1.63 mmol) and DMF (15 mL), then DIPEA (1.42mL, 8.15 mmol) was added dropwise. After 1 h, the mixture was dilutedwith EtOAc and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (0% to 30% MeOH/EtOAc) to afford methyl[(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate(596 mg, 57%).

Tert-butyl(2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

Methyl[(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate(298 mg, 0.47 mmol), (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (443 mg, 1.4mmol), Pd(PPh₃)₄ (54 mg, 0.05 mmol), PdCl₂(dppf)₂ (36 mg, 0.05 mmol),and K₂CO₃ (2M in H₂O, 0.78 mL, 1.55 mmol) were combined in DME (5 mL).The mixture was degassed with bubbling N₂ for 10 min the heated to 85°C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc,and washed successively with saturated aqueous NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(0% to 30% MeOH/EtOAc) to afford tert-butyl(2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(84 mg, 24%).

Methyl{(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

Tert-butyl(2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(84 mg, 0.11 mmol) was dissolved in DCM (2.5 mL), MeOH (0.5 mL) and HCl(4 M in dioxane, 0.5 mL) was added. The reaction mixture was stirred for18 h and then concentrated under reduced pressure. The crude residue wastreated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (23 mg,0.11 mmol), COMU (53 mg, 0.11 mmol) and DMF (3 mL), then DIPEA (0.10 mL,0.56 mmol) was added dropwise. After 30 min, the mixture was dilutedwith 10% MeOH/EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byHPLC to afford methyl{(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(41 mg, 45%). LCMS-ESI⁺: calculated for C47H50N8O7: 838.38. observed[M+1]⁺: 839.39.

Example NC

Methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(164 mg, 0.23 mmol) was dissolved in DCM (2.57 mL), MeOH (0.7 mL) andHCl (4 M in dioxane, 0.7 mL) was added. The reaction mixture was stirredfor 16 h and then concentrated under reduced pressure. The crude residuewas treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (30mg, 0.17 mmol), HATU (65 mg, 0.17 mmol) and DMF (3 mL), then DIPEA (0.15mL, 0.85 mmol) was added dropwise. After 45 min, the mixture was dilutedwith 10% MeOH/EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byHPLC to afford methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(23 mg, 16%).

LCMS-ESI⁺: calculated for C45H54N8O7: 818.41. observed [M+1]⁺: 820.70.

Example ND

Tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(293 mg, 0.0.78 mmol), (2S,4S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (300 mg,0.52 mmol), Pd(PPh₃)₄ (60 mg, 0.052 mmol), PdCl₂(dppf)₂ (38 mg, 0.052mmol), and K₂CO₃ (2M in H₂O, 0.86 mL, 1.72 mmoL) were combined in DME (6mL). The mixture was degassed with bubbling N₂ for 10 min the heated to85° C. for 16 h. After cooling, the reaction mixture was diluted withEtOAc, and washed successively with saturated aqueous NaHCO₃ and brine.The organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude residue was purified by silica columnchromatography (100% EtOAc) to afford tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(183 mg, 50%).

Methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(183 mg, 0.26 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 2 hand then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (91 mg,0.52 mmol), HATU (198 mg, 0.52 mmol) and DMF (5 mL), then DIPEA (0.45mL, 2.6 mmol) was added dropwise. After 1 h, the mixture was dilutedwith 10% MeOH/EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byHPLC to afford methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(6 mg, 3%). LCMS-ESI⁺: calculated for C45H54N8O7: 818.41. observed[M+1]⁺: 819.41.

Example NE

(2S,4S)-benzyl2-(5-(4′-(2-(tert-butoxycarbonylamino)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

(2S,4S)-benzyl4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(500 mg, 0.97 mmol), tert-butyl 2-(4-bromophenyl)-2-oxoethylcarbamate(364 mg, 1.16 mmol), Pd(PPh₃)₄ (112 mg, 0.097 mmol), and K₂CO₃ (2M inH₂O, 1.6 mL, 3.2 mmoL) were combined in DME (10 mL). The mixture wasdegassed with bubbling N₂ for 10 min the heated to 85° C. for 18 h.After cooling, the reaction mixture was diluted with EtOAc, and washedsuccessively with saturated aqueous NaHCO₃ and brine. The organics weredried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (0% to 30%MeOH/EtOAc) to afford product (357 mg, 56%).

(2S,4S)-benzyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

(2S,4S)-benzyl2-(5-(4′-(2-(tert-butoxycarbonylamino)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(640 mg, 1.02 mmol) was dissolved in DCM (8 mL), MeOH (2 mL) and HCl (4M in dioxane, 2 mL) was added. The reaction mixture was stirred for 14 hand then concentrated under reduced pressure. The crude residue wastreated with(2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylicacid (324 mg, 1.02 mmol), HATU (388 mg, 1.02 mmol) and DMF (10 mL), thenDIPEA (0.9 mL, 5.12 mmol) was added dropwise. After 1 h, the mixture wasdiluted with EtOAc and washed successively with saturated aqueous NaHCO₃and brine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (0% to 30% MeOH/EtOAc) to afford (2S,4S)-benzyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(487 mg, 58%).

(2S,4S)-benzyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

To (2S,4S)-benzyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(487 mg, 0.59 mmol) was added PhMe (6 mL), MeOEtOH (1 mL), and ammoniumacetate (0.91 g, 11.8 mmol) and the solution was heated to 110° C. Thesolution was stirred for 3 h and then cooled to rt and was diluted withEtOAc and washed successively with water, saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (0% to 30% MeOH/EtOAc) to afford (2S,4S)-benzyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(276 mg, 58%).

Methyl(S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(2S,4S)-benzyl2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(220 mg, 0.27 mmol) was dissolved in DCM (5 mL), MeOH (0.4 mL) andcooled to 0° C. HBr (33% in AcOH, 1 mL) was added dropwise. Afterstirring for 1 hr, the mixture was concentrated under reduced pressure,coevaporating with PhMe. The crude residue was treated with(R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (68 mg, 0.27 mmol),COMU (129 mg, 0.27 mmol) and DMF (5 mL), then DIPEA (0.24 mL, 1.35 mmol)was added dropwise. After 1 h, the mixture was diluted with EtOAc andwashed successively with saturated aqueous NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(0% to 40% MeOH/EtOAc) to afford methyl(S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(179 mg, 73%).

Methyl(S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-(tert-butoxycarbonylamino)-2-phenylacety)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(179 mg, 0.20 mmol) was dissolved in DCM (5 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 20 hand then concentrated under reduced pressure. The crude residue wastreated with cyclopropanecarboxylic acid (16 μL, 0.20 mmol), COMU (96mg, 0.20 mmol) and DMF (5 mL), then DIPEA (0.17 mL, 1.0 mmol) was addeddropwise. After 30 min, the mixture was diluted with 10% MeOH/EtOAc andwashed successively with saturated aqueous NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by HPLC to afford methyl(S)-1-((2S,4S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methylthio)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(34 mg, 20%). LCMS-ESI⁺: calculated for C48H56N8O6S: 872.40. observed[M+1]⁺: 874.38.

Example NF

Tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate

(2S,4S)-tert-butyl-2-(9-(2-((S)-1-((S)-2-(methoxycarbonylamino)methylbutanoyl)azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(558 mg, 0.96 mmol), methyl(S)-1-((2S,4S)-2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(501 mg, 1.15 mmol), Pd(PPh₃)₄ (111 mg, 0.096 mmol), PdCl₂(dppf)₂ (70mg, 0.096 mmol), and K₂CO₃ (2M in H₂O, 1.6 mL, 3.17 mmoL) were combinedin DMSO (6 mL) and dioxane (6 mL). The mixture was degassed withbubbling N₂ for 10 min the heated to 95° C. for 14 h. After cooling, thereaction mixture was diluted with EtOAc, and washed successively withsaturated aqueous NaHCO₃ and brine. The organics were dried over MgSO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (0%-30% MeOH/EtOAc) to affordtert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(257 mg, 35%).

Methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(257 mg, 0.34 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 3 hand then concentrated under reduced pressure. The crude residue wastreated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (71 mg,0.34 mmol), COMU (161 mg, 0.34 mmol) and DMF (6 mL), then DIPEA (0.3 mL,1.67 mmol) was added dropwise. After 15 h, the mixture was diluted with10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by HPLC to affordmethyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(152 mg, 53%). LCMS-ESI⁺: calculated for C48H₅₂N8O7: 852.40. observed[M+1]⁺: 854.26. ¹H NMR (CD₃OD): 8.677 (s, 1H), 8.232-7.837 (m, 5H),7.695-7.673 (m, 2H), 7.496-7.426 (m, 5H), 5.499 (s, 1H), 5.445-5.401 (m,1H), 5.337 (s, 1H), 5.253-5.208 (q, 1H, J=7.2 Hz), 4.870 (m, 1H), 4.230(d, 1H, J=7.2 Hz), 3.781 (m, 1H), 3.671 (s, 3H), 3.607 (s, 3H), 3.425(m, 3H), 2.750-2.689 (m, 2H), 2.683 (m, 2H), 2.384 (m, 1H), 1.894(quint, 2H, J=12 Hz), 1.249-1.151 (m, 6H), 0.974-0.890 (m, 6H).

Example NG

(2S,5S)-1-tert-butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)5-methylpyrrolidine-1,2-dicarboxylate

To a solution of3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one in MeCN(30 mL) was added(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(1.2 g, 3.23 mmol) and triethyl amine (0.48 mL, 3.55 mmol) and thesolution was heated to 50° C. After stirring for 15 h, the solution wascooled to rt, and diluted with EtOAc and washed successively withsaturated aqueous NaHCO₃ and brine. The organics were dried over MgSO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (20% to 50% EtOAc/hexanes) toafford (2S,5S)-1-tert-butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)5-methylpyrrolidine-1,2-dicarboxylate (1.09 g, 65%).

(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate

(2S,5S)-1-tert-butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)5-methylpyrrolidine-1,2-dicarboxylate (1.29 g, 2.48 mmol) was dissolvedin a solution of DCM (17.5 mL) and MeOH (7 mL), then treated withpyridinium tribromide (873 mg, 2.73 mmol). After stirring at RT for 1 h,the reaction mixture was diluted with DCM and 10% HCl, and extractedwith DCM. The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure and the crude material was carriedon without further purification.

(2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate

(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (700 mg, 1.17 mmol)was treated with a solution of(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(375 mg, 1.64 mmol) in acetone (6 mL) and Cs₂CO₃ (267 mg, 0.82 mmol).The stirred reaction mixture was heated to 40° C. for 16 h, then cooledto RT and diluted with CH₂Cl₂ and extracted 3×. The organic phase waswashed with brine, then dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (40% to 100% EtOAc/hexanes) to afford(2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (464 mg, 53%).

Tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

(2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (464 mg, 0.62 mmol)and NH₄OAc (8.48 g, 110.0 mmol) were suspended in a solution of 10:1PhMe/2-methoxyethanol (22 mL). The stirred reaction mixture was heatedto 110° C. for 20 h, then cooled to RT and diluted with EtOAc. Theorganic phase was washed with water, saturated aqueous NaHCO₃, andbrine, then dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(0% to 30% MeOH/EtOAc) to afford tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(393 mg, 90%).

Tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

Tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(393 mg, 0.55 mmol) was suspended in DCM (7 mL) and activated MnO₂ (1.45g, 16.7 mmol) was added in a single portion. The reaction mixture washeated to 40° C. After stirring for 2.5 h, the mixture was cooled to rtand the slurry was filtered over celite. The filter cake was washed withcopious CH₂Cl₂ and MeOH and the filtrate was concentrated under reducedpressure. The crude material was taken on to the next step withoutfurther purification to afford tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(328 g, 85%).

Methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(164 mg, 0.23 mmol) was dissolved in DCM (7 mL), MeOH (1.5 mL) and HCl(4 M in dioxane, 1.5 mL) was added. The reaction mixture was stirred for16 h and then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (81 mg,0.46 mmol), HATU (175 mg, 0.46 mmol) and DMF (5 mL), then DIPEA (0.4 mL,2.34 mmol) was added dropwise. After 35 min, the mixture was dilutedwith 10% MeOH/EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byHPLC to afford methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(132 mg, 69%). LCMS-ESI⁺: calculated for C45H54N8O7: 818.41. observed[M+1]⁺: 820.19. ¹H NMR (CD₃OD): 8.492 (m, 1H), 8.179-7.538 (m, 7H),5.267-5.201 (m, 3H), 5.125-5.082 (m, 1H), 4.070 (m, 1H), 3.383-3.592 (m,4H), 3.225 (s, 3H), 2.466-2.249 (m, 5H), 1.992-1.892 (m, 3H), 1.568 (d,3H, J=6.4 Hz), 1.490 (d, 3H, J=6.8 Hz), 1.266 (m, 2H), 1.020-0.806 (m,14H).

Example NH

(2S,5S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl5-methylpyrrolidine-1,2-dicarboxylate

To a solution of 2-bromo-1-(4-bromophenyl)ethanone (505 mg, 1.82 mmol)in MeCN (18 mL) was added(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(500 mg, 2.18 mmol) and triethyl amine (0.27 mL, 2.0 mmol). Afterstirring for 15 h, the solution was diluted with EtOAc and washedsuccessively with saturated aqueous NaHCO₃ and brine. The organics weredried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (10% to 40%EtOAc/hexanes) to afford (2S,5S)-2-(2-(4-bromophenyl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (640 mg, 82%).

(2S,5S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

(2S,5S)-2-(2-(4-bromophenyl)-2-oxoethyl) 1-tert-butyl5-methylpyrrolidine-1,2-dicarboxylate (640 mg, 1.5 mmol) was added PhMe(12 mL), MeOEtOH (3 mL) and ammonium acetate (2.3 g, 30 mmol) and thesolution was heated to 110° C. After stirring for 2 h, the solution wascooled to rt and was diluted with EtOAc and washed successively withwater, saturated aqueous NaHCO₃ and brine. The organics were dried overMgSO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography (100% EtOAc) toafford (2S,5S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(562 mg, 92%).

Methyl(S)-1-((2S,5S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(2S,5S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(562 mg, 1.38 mmol) was dissolved in DCM (8 mL), MeOH (2 mL) and HCl (4M in dioxane, 2 mL) was added. The reaction mixture was stirred for 4 hand then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (241 mg,1.38 mmol), HATU (525 mg, 1.38 mmol) and DMF (14 mL), then DIPEA (1.2mL, 6.9 mmol) was added dropwise. After 30 min, the mixture was dilutedwith EtOAc and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (0% to 10% MeOH/EtOAc) to afford methyl(S)-1-((2S,5S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(503 mg, 79%).

(2S,4S)-tert-butyl2-(5-(4′-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

(2S,4S)-tert-butyl4-(methoxymethyl)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(461 mg, 095 mmol), methyl(S)-1-((2S,5S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(503 mg, 1.08 mmol) Pd(PPh₃)₄ (110 mg, 0.095 mmol), PdCl₂(dppf)₂ (70 mg,0.095 mmol), and K₂CO₃ (2M in H₂O, 1.56 mL, 3.1 mmoL) were combined inDME (10 mL). The mixture was degassed with bubbling N₂ for 10 min theheated to 85° C. for 16 h. After cooling, the reaction mixture wasdiluted with EtOAc, and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (0% to 30% MeOH/EtOAc) to afford(2S,4S)-tert-butyl2-(5-(4′-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatecarboxylate(289 mg, 41%).

Tert-butyl(R)-2-((2S,4S)-2-(5-(4′-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

(2S,4S)-tert-butyl2-(5-(4′-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(289 mg, 0.39 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 2 hand then concentrated under reduced pressure. The crude residue wastreated with (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (98mg, 0.39 mmol), COMU (186 mg, 0.39 mmol) and DMF (5 mL), then DIPEA(0.34 mL, 1.96 mmol) was added dropwise. After 30 min, the mixture wasdiluted with EtOAc and washed successively with saturated aqueous NaHCO₃and brine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (0% to 30% MeOH/EtOAc) to afford tert-butyl(R)-2-((2S,4S)-2-(5-(4′-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(201 mg, 59%).

Methyl(S)-1-((2S,5S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Tert-butyl(R)-2-((2S,4S)-2-(5-(4′-(2-((2S5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(201 mg, 0.23 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 4 hand then concentrated under reduced pressure. The crude residue wastreated with cyclopropanecarboxylic acid (18 μL, 0.23 mmol), COMU (110mg, 0.23 mmol) and DMF (5 mL), then DIPEA (0.20 mL, 1.15 mmol) was addeddropwise. After 30 min, the mixture was diluted with 10% MeOH/EtOAc andwashed successively with saturated aqueous NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by HPLC to afford methyl(S)-1-((2S,5S)-2-(5-(4′-(2-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(25 mg, 13%). LCMS-ESI⁺: calculated for C48H56N8O6: 840.43. observed[M+1]⁺: 842.39.

Example NI

Methyl[(2S,3R)-3-methoxy-1-{(2S,5S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate

Tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(164 mg, 0.23 mmol) was dissolved in DCM (7 mL), MeOH (1.5 mL) and HCl(4 M in dioxane, 1.5 mL) was added. The reaction mixture was stirred for16 h and then concentrated under reduced pressure. The crude residue wastreated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (90mg, 0.46 mmol), HATU (175 mg, 0.46 mmol) and DMF (6 mL), then DIPEA (0.4mL, 2.34 mmol) was added dropwise. After 30 min, the mixture was dilutedwith 10% MeOH/EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byHPLC to afford methyl[(2S,3R)-3-methoxy-1-{(2S,5S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate(97 mg, 50%). LCMS-ESI⁺: calculated for C45H54N8O9: 850.40; observed[M+1]⁺: 851.58. ¹H NMR (CD₃OD): 8.631 (s, 1H), 8.191-7.938 (m, 7H),6.100 (m, 1H), 5.925 (m, 1H), 5.303 (m, 3H), 5.179 (t, 1H, J=6.8 Hz),4.406-4.358 (m, 2H), 3.754-3.598 (m, 8H), 3.376 (s, 3H), 3.263 (s, 3H),2.625-2.256 (m, 6H), 2.038-1.955 (m, 2H), 1.598 (d, 3H, J=6.4 Hz), 1.530(d, 3H, J=6.8 Hz), 1.302-1.099 (m, 6H).

Example NJ

(2S,5S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate

(2S,5S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (800 mg, 1.34 mmol)was treated with a solution of(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (485 mg, 1.87 mmol) in acetone (6 mL) and Cs₂CO₃ (306 mg, 0.94mmol). The stirred reaction mixture was heated to 40° C. for 16 h, thencooled to RT and diluted with CH₂Cl₂ and extracted 3×. The organic phasewas washed with brine, then dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (40% to 100% EtOAc/hexanes) to afford(2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-R-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (680 mg, 65%).

Tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

(2S,5S)-2-(2-(9-((2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (680 mg, 0.87 mmol)and NH₄OAc (10.0 g, 130.0 mmol) were suspended in a solution of 10:1PhMe/2-methoxyethanol (22 mL). The stirred reaction mixture was heatedto 110° C. for 24 h, then cooled to RT and diluted with EtOAc. Theorganic phase was washed with water, saturated aqueous NaHCO₃, andbrine, then dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(0% to 30% MeOH/EtOAc) to afford tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(461 mg, 72%).

Tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

Tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(461 mg, 0.62 mmol) was suspended in DCM (7 mL) and activated MnO₂ (1.6g, 18.8 mmol) was added in a single portion. The reaction mixture washeated to 40° C. After stirring for 5.5 h, the mixture was cooled to rtand the slurry was filtered over celite. The filter cake was washed withcopious CH₂Cl₂ and MeOH and the filtrate was concentrated under reducedpressure. The crude material was taken on to the next step withoutfurther purification to afford tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(414 g, 90%).

Methyl{(2S,3S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate

Tert-butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(207 mg, 0.28 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 1.5h and then concentrated under reduced pressure. The crude residue wastreated with (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid(106 mg, 0.56 mmol), HATU (214 mg, 0.56 mmol) and DMF (5 mL), then DIPEA(0.49 mL, 2.8 mmol) was added dropwise. After 30 min, the mixture wasdiluted with 10% MeOH/EtOAc and washed successively with saturatedaqueous NaHCO₃ and brine. The organics were dried over MgSO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedby HPLC to afford methyl{(2S,3S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate(132 mg, 69%). LCMS-ESI⁺: calculated for C45H54N8O7: 876.45. observed[M+1]⁺: 879.02.

Example NK

(2S,4S)-1-tert-butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)4-methylpyrrolidine-1,2-dicarboxylate

To a solution of3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (647mg, 1.74 mmol) in MeCN (20 mL) was added((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(559 mg, 2.44 mmol) and DIPEA (0.36 mL, 2.09 mmol) and the solution washeated to 60° C. After stirring for 3 h, the solution was cooled to rt,and diluted with EtOAc and washed successively with saturated aqueousNaHCO3 and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (20% to 50% EtOAc/hexanes) to afford(2S,4S)-1-tert-butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)4-methylpyrrolidine-1,2-dicarboxylate (621 mg, 69%).

(2S,4S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate

(2S,4S)-1-tert-butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)4-methylpyrrolidine-1,2-dicarboxylate (621 mg, 1.19 mmol) was dissolvedin a solution of DCM (10 mL) and MeOH (4 mL), then treated withpyridinium tribromide (421 mg, 1.3 mmol). After stirring at RT for 1.5h, the reaction mixture was diluted with DCM and 10% HCl, and extractedwith DCM. The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure and the crude material was carriedon without further purification.

(2S,4S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate

(2S,4S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (709 mg, 1.18 mmol)was treated with a solution of(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (614 mg, 2.36 mmol) in Me-THF (12 mL) and Cs₂CO₃ (384 mg, 1.18mmol). The stirred reaction mixture was heated to 50° C. for 16 h, thencooled to RT and diluted with CH₂Cl₂ and extracted 3×. The organic phasewas washed with brine, then dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (40% to 100% EtOAc/hexanes) to afford(2S,4S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (651 mg, 71%).

Tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

(2S,4S)-2-(2-(9-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (651 mg, 0.84 mmol)and NH₄OAc (10.0 g, 129.7 mmol) were suspended in a solution of 10:1PhMe/2-methoxyethanol (22 mL). The stirred reaction mixture was heatedto 110° C. for 20 h, then cooled to RT and diluted with EtOAc. Theorganic phase was washed with water, saturated aqueous NaHCO₃, andbrine, then dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(0% to 30% MeOH/EtOAc) to afford tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(382 mg, 62%).

Tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate

Tert-butyl(2S,5S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (382mg, 0.52 mmol) was suspended in DCM (8 mL) and activated MnO₂ (1.35 g,15.5 mmol) was added in a single portion. The reaction mixture washeated to 35° C. After stirring for 15 h, the mixture was cooled to rtand the slurry was filtered over celite. The filter cake was washed withcopious CH₂Cl₂ and MeOH and the filtrate was concentrated under reducedpressure. The crude material was taken on to the next step withoutfurther purification to afford tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(347 g, 91%).

Methyl{(2S,3R)-3-methoxy-1-[(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(174 mg, 0.24 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 5 hand then concentrated under reduced pressure. The crude residue wastreated with ((2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid(92 mg, 0.48 mmol), HATU (182 mg, 0.48 mmol) and DMF (5 mL), then DIPEA(0.31 mL, 2.4 mmol) was added dropwise. After 35 min, the mixture wasdiluted with 10% MeOH/EtOAc and washed successively with saturatedaqueous NaHCO₃ and brine. The organics were dried over MgSO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedby HPLC to afford methyl{(2S,3R)-3-methoxy-1-[(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate(72 mg, 34%). LCMS-ESI⁺: calculated for C46H56N8O10: 880.41. observed[M+1]⁺: 882.39. ¹H NMR (CD₃OD): 8.558 (s, 1H), 8.123-7.572 (m, 7H),5.436-5.391 (dd, 1H, J=7.2, 3.6 Hz), 5.252 (s, 2H), 5.220 (m, 1H),4.493-4.444 (m, 2H), 4.287-4.206 (m, 2H), 3.756-3.256 (m, 2H), 2.834 (m,1H), 2.717-2.621 (m, 2H), 2.500 (m, 1H), 2.150 (m, 1H), 1.882 (m, 1H),1.208 (d, 3H, J=6.4 Hz), 1.159-1.099 (m, 6H).

Example NL

(2S,5S)-2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate

To a solution of3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (750mg, 2.02 mmol) in MeCN (20 mL) was added(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid (600 mg, 2.09 mmol) and DIPEA (0.35 mL, 2.02 mmol) and the solutionwas heated to 60° C. After stirring for 4 h, the solution was cooled tort, and diluted with EtOAc and washed successively with saturatedaqueous NaHCO₃ and brine. The organics were dried over MgSO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedby silica column chromatography (40% to 80% EtOAc/hexanes) to afford(2S,5S)-2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate(1.16 g, quant.).

(2S,5S)-2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate

(2S,5S)-2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate(400 mg, 0.61 mmol) was dissolved in a solution of DCM (15 mL) and MeOH(6 mL), then treated with pyridinium tribromide (409 mg, 1.28 mmol). At2 h, an additional portion of pyridinium tribromide (40 mg) was added.After stirring at RT for another 20 min, the reaction mixture wasdiluted with DCM and 10% HCl, and extracted with DCM. The organic phasewas dried over MgSO₄, filtered and concentrated under reduced pressureand the crude material was carried on without further purification.

(2S,4S)-1-tert-butyl2-(3-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-methylpyrrolidine-1,2-dicarboxylate

(2S,5S)-2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate)was treated with a solution of(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(280 mg, 1.22 mmol) in Me-THF (6 mL) and Cs₂CO₃ (199 mg, 0.61 mmol). Thestirred reaction mixture was heated to 50° C. for 2.5 h, then cooled toRT and diluted with CH₂Cl₂ and extracted 3×. The organic phase waswashed with brine, then dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (50% to 100% EtOAc/hexanes) to afford(2S,4S)-1-tert-butyl2-(3-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-methylpyrrolidine-1,2-dicarboxylate (441 mg, 90%).

Tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate

(2S,4S)-1-tert-butyl2-(3-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-methylpyrrolidine-1,2-dicarboxylate (441 mg, 0.55 mmol) and NH₄OAc (5g, 65.0 mmol) were suspended in a solution of 10:1 PhMe/2-methoxyethanol(11 mL). The stirred reaction mixture was heated to 110° C. for 7 h,then cooled to RT and diluted with EtOAc. The organic phase was washedwith water, saturated aqueous NaHCO₃, and brine, then dried over MgSO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (0% to 30% MeOH/EtOAc) toafford tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(266 mg, 63%).

Tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate

Tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,4,5,11tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(266 mg, 0.35 mmol) was suspended in DCM (7 mL) and activated MnO₂ (908mg, 10.45 mmol) was added in a single portion. The reaction mixture wasstirred overnight. After stirring for 15 h, additional activated MnO₂(500 mg, 5.75 mmol) was added in a single portion. After stirring 2 h at35° C., the mixture was cooled to rt and the slurry was filtered overcelite. The filter cake was washed with copious CH₂Cl₂ and MeOH and thefiltrate was concentrated under reduced pressure. The crude material wastaken on to the next step without further purification to affordtert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(266 mg, quant).

Methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S,3R)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(266 mg, 0.23 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 1.5h and then concentrated under reduced pressure. The crude residue wastreated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (44mg, 0.23 mmol), HATU (87 mg, 0.23 mmol) and DMF (5 mL), then DIPEA (0.3mL, 1.75 mmol) was added dropwise. After 30 min, the mixture was dilutedwith 10% MeOH/EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byHPLC to afford methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(59 mg, 31%). LCMS-ESI⁺: calculated for C45H54N8O8: 834.41. observed[M+1]⁺: 836.89. ¹H NMR (CD₃OD): 8.186 (s, 1H), 7.800-7.291 (m, 7H),5.258-5.213 (dd, 1H, J=7.2, 3.6 Hz), 5.027-4.918 (m, 4H), 4.620 (t, 1H,J=6.8 Hz), 4.246 (m, 1H), 4.116 (m, 1H), 3.972 (d, 1H, J=8.8 Hz),3.701-3.675 (m, 1H), 3.503 (s, 3H), 3.479 (s, 3H), 3.177 (s, 3H),2.554-2.191 (m, 3H), 1.906-1.821 (m, 6H), 1.392 (d, 2H, J=6.4 Hz),1.113-0.728 (m, 12H).

Example NM

Tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

Methyl[(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate(312 mg, 0.49 mmol), methyl(S)-1-((2S,4S)-2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(219 mg, 0.54 mmol), Pd(PPh₃)₄ (58 mg, 0.05 mmol), PdCl₂(dppf)₂ (36 mg,0.05 mmol), and K₂CO₃ (2M in H₂O, 0.8 mL, 1.6 mmoL) were combined inDMSO (5 mL) and dioxane (5 mL). The mixture was degassed with bubblingN₂ for 10 min the heated to 95° C. for 5 h. After cooling, the reactionmixture was diluted with EtOAc, and washed successively with saturatedaqueous NaHCO₃ and brine. The organics were dried over MgSO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedby silica column chromatography (0%-30% MeOH/EtOAc) to afford tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(166 mg, 43%).

Methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

Tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(166 mg, 0.21 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 2 hand then concentrated under reduced pressure. The crude residue wastreated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (44 mg,0.21 mmol), COMU (100 mg, 0.21 mmol) and DMF (5 mL), then DIPEA (0.18mL, 1.05 mmol) was added dropwise. After 1 h, the mixture was dilutedwith 10% MeOH/EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byHPLC to afford methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(71 mg, 38%). LCMS-ESI⁺: calculated for C49H54N8O8: 882.41; observed[M+1]⁺: 884.34. ¹H NMR (CD₃OD): 8.462 (s, 1H), 8.029-7.471 (m, 7H),7.394-7.343 (m, 5H), 5.410 (d, 2H, J=6.8 Hz), 5.300 (m, 1H), 5.233 (m,2H), 4.341 (m, 1H), 4.236 (d, 1H, J=7.2 Hz), 3.603 (s, 3H), 3.551 (s,3H), 3.522-3.241 (m, 8H), 2.650 (m, 1H), 2.550 (m, 2H), 1.977-1.926 (m,4H), 1.221 (d, 3H, J=3.2 Hz), 0.897-0.779 (dd, 6H, J=19.2, 6.8 Hz).

Example NN

2,6-dibromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one

To a solution of 6-bromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one (900mg, 3.7 mmol) in CHCl₃ (25 mL) and EtOAc (25 mL) was added copper IIbromide (1.65 g, 7.4 mmol), and the mixture was heated to 80° C. for 7h. After heating, the mixture was cooled to rt, diluted with CH₂Cl₂ andsaturated aqueous NH₄Cl and separated. The organics were dried overMgSO₄, filtered and concentrated under reduced pressure. The cruderesidue was taken on to the next step with out purification.

(2S)-2-(6-bromo-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)1-tert-butyl pyrrolidine-1,2-dicarboxylate

To a solution of 2,6-dibromo-5-fluoro-3,4-dihydronaphthalen-1(2H)-one inMeCN (30 mL) was added(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.12g, 5.2mmol) and triethyl amine (0.62 mL, 4.48 mmol) and the solution washeated to 55° C. After stirring for 15 h, the solution was cooled to rt,and diluted with EtOAc and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (10% to 35% EtOAc/hexanes) to afford(2S)-2-(6-bromo-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (648 mg, 38%).

(S)-tert-butyl2-(7-bromo-6-fluoro-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

To (2S)-2-(6-bromo-5-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (773 mg, 1.69 mmol) was addedPhMe (15 mL) and ammonium acetate (2.6 g, 33.88 mmol) and the solutionwas heated to 110° C. and stirred overnight. The following morning, thesolution was cooled to rt and was diluted with EtOAc and washedsuccessively with water, saturated aqueous NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(40% to 100% EtOAc/hexanes) to afford (S)-tert-butyl2-(7-bromo-6-fluoro-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(648 mg, 88%).

(S)-tert-butyl2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl2-(7-bromo-6-fluoro-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(324 mg, 0.74 mmol) in benzene (7 mL) was added DDQ (185 mg, 0.82 mmol)and the mixture was heated to 80° C. After stirring for 16 h, thereaction mixture was cooled to rt and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(45% to 100% EtOAc/hexanes) to afford (S)-tert-butyl2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(204 mg, 63%).

Methyl(S)-1-((S)-2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-tert-butyl2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(204 mg, 0.47 mmol) was dissolved in DCM (5 mL), MeOH (1 mL) and HCl (4M in dioxane, 1 mL) was added. The reaction mixture was stirred for 16 hand then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (82 mg,0.47 mmol), HATU (179 mg, 0.47 mmol) and DMF (6 mL), then DIPEA (0.41mL, 2.35 mmol) was added dropwise. After 3 h, the mixture was dilutedwith EtOAc and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (0% to 30% MeOH/EtOAc) to afford methyl(S)-1-((S)-2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(238 mg, 49%).

(S)-tert-butyl2-(6′-fluoro-2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-butyl2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(250 mg, 0.48 mmol) and methyl(S)-1-((S)-2-(7-bromo-6-fluoro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(200 mg, 0.4 mmol), Pd(PPh₃)₄ (46 mg, 0.04 mmol), Pd(dppf)₂Cl₂ (29 mg,0.04 mmol), and K₂CO₃ (2M in H₂O, 0.67 mL, 1.34 mmoL) were combined inDME (6 mL). The mixture was degassed with bubbling N₂ for 10 min theheated to 85° C. for 16 h. After cooling, the reaction mixture wasdiluted with EtOAc, and washed successively with saturated aqueousNaHCO₃ and brine. The organics were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (0% to 30% MeOH/EtOAc) to afford(S)-tert-butyl2-(6′-fluoro-2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(213 mg, 71%).

Dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(6-fluoro-1H,1′H-7,7′-binaphtho[1,2-d]imidazole-2,2′-diyl)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)Dicarbamate

(S)-tert-butyl2-(6′-fluoro-2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(213 mg, 0.28 mmol) was dissolved in DCM (7 mL), MeOH (1.5 mL) and HCl(4 M in dioxane, 1.5 mL) was added. The reaction mixture was stirred for2 h and then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (49 mg,0.28 mmol), HATU (106 mg, 0.28 mmol) and DMF (5 mL), then DIPEA (0.25mL, 1.42 mmol) was added dropwise. After 35 min, the mixture was dilutedwith EtOAc and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by HPLC to afforddimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(6-fluoro-1H,1′H-7,7′-binaphtho[1,2-d]imidazole-2,2′-diyl)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(126 mg, 56%). LCMS-ESI⁺: calculated for C44H49FN8O6: 804.38. observed[M+1]⁺: 805.41.

Example NO

(S)-ethyl 2-(tert-butoxycarbonylamino)-5-oxohexanoate

A solution of ethyl N-Boc (S)-pyroglutamate (20.0 g, 77.7 mmol) was inanhydrous THF (150 mL) in a two neck round bottom under argon was cooledto −40° C. Methyl-magnesium bromide solution (3.0 M in Ether, 28.5 mL,85.5 mmol) was added to the reaction mixture dropwise over 30 minutes.The reaction was stirred for 4 hrs at −40° C. then for 1 hr at 0° C. Thereaction was partitioned between ethyl acetate and saturated ammoniumchloride solution and acidified with 1 N HCl. The aqueous layer wasextracted two more times with ethylacetate. The organic layers werecombined and dried with sodium sulfate. The crude material was purifiedby column chromatography (20%-40% EtOAc/hexanes) to yield (S)-ethyl2-(tert-butoxycarbonylamino)-5-oxohexanoate as a viscous oil and wasused directly in the following step.

(S)-ethyl 5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate

(S)-ethyl 2-(tert-butoxycarbonylamino)-5-oxohexanoate in a 1 L flask wastreated with a trifluoro acetic acid/dichloromethane solution (1:1mixture, 100 mL). Effervescence was observed and the mixture was allowedto stir for 4 hours at room temperature. After which time the volatileswere removed in vacuo to yield (S)-ethyl5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate as an oil, and useddirectly in the following step.

(2S,5S)-ethyl 5-methylpyrrolidine-2-carboxylate

The crude imine in a 1 L flask was dissolved with ethanol (400 mL) wasevacuated and charged with argon three times (3×). Palladium on carbon(apprx. 750 mg, 10% w/w, dry) was added and the reaction was evacuatedof gas and charged with hydrogen gas (3×). The reaction was allowed tostir under atmospheric hydrogen for 16 hours. The mixture was filteredthrough a plug of celite and the filtrate was concentrated in vacuo.Diethyl ether was added to the oil and a precipitate formed. The mixturewas filtered to yield (2S,5S)-ethyl 5-methylpyrrolidine-2-carboxylate,as a white solid (10.6 g, 67.4 mmol, 86.7% over three steps). ¹H NMR(400 MHz, cdcl₃) δ 4.48 (dd, 1H), 4.27 (q, 2H), 3.92-3.80 (m, 1H),2.52-2.36 (m, 1H), 2.32-2.13 (m, 2H), 1.75-1.60 (m, 1H), 1.51 (d, 3H),1.30 (t, 3H).

(2S,5S)-1-tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate

To a solution of (2S,5S)-ethyl 5-methylpyrrolidine-2-carboxylate (7.0 g,44.5 mmol) in dichloromethane (250 mL), ditertbutylanhydride (10.7 g,49.0 mmol), diisopropylethylamine (17.1 mL, 98.0 mmol) dropwise over 10minutes, and dimethyl amino pyridine (0.27 g, 2.23 mmol) were addedsuccessively. Effervescence was observed and the mixture was allowed tostir for 16 hours at room temperature. The reaction was washed with HCl(250 mL, of 1N). The organic layer was then dried with sodium sulfate.The crude material was purified by column chromatography (5%-25%EtOAc/hexanes) to yield (2S,5S)-1-tert-butyl 2-ethyl5-methylpyrrolidine-1,2-dicarboxylate as an oil (6.46 g, 25.1 mmol,56%). LCMS-ESI⁺: calc'd for C₁₃H₂₃NO₄: 257.16 (M⁺). Found: 258.70(M+H⁺).

(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid

To a solution of (2S,5S)-1-tert-butyl 2-ethyl5-methylpyrrolidine-1,2-dicarboxylate (6.46 g, 25.1 mmol) in ethanol (20mL) was added lithium hydroxide mono hydrate (2.11 g, 50.2 mmol) anddeionized water (12 mL). The mixture was allowed to stir for 16 hoursthen partitioned between ethylacetate and a 1:1 mixture of saturatedbrine and 1N HCl. The aqueous layer was extracted an additional timewith ethyl acetate. The organic layers were combined, dried with sodiumsulfate and the solvent was removed in vacuo to yield(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid asa white solid (quant.) and was used directly in the following step.

(2S,5S)-tert-butyl 2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate

To a solution of(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(5.91 g, 25.8 mmol) in tetrahydrofuran at 0° C., was added borane indimethylsulfide (1.0 M, 3.4 mL, 34 mmol) dropwise. The reaction wasstirred for 4 hours at 0° C. then 18 hours at room temperature. Themixture was then cooled to 0° C. and methanol (70 mL) was addeddropwise. The reaction was warmed to room temperature and the solventswere removed in vacuo. The residue was taken up in dichloromethane (200mL) and extracted with saturated sodium bicarbonate. The organic layerwas dried with sodium sulfate and the solvent was removed in vacuo toyield (2S,5S)-tert-butyl2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate as a clear oil (5.15g, 23.9 mmol, 93%) and was used directly in the following step.

(2S,5S)-tert-butyl 2-formyl-5-methylpyrrolidine-1-carboxylate

To a solution of (2S,5S)-tert-butyl2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate (5.15 g, 23.9 mmol)in dichloromethane, was added TEMPO (0.075 g, 0.48 mmol), sodium bromide(0.246 g, 2.39 mmol) and sodium bicarbonate (0.442 g, 5.26 mmol). Sodiumhypochlorite (2.67 g, 35.9 mmol) of a 6% solution was added and thebiphasic mixture was vigorously stirred for 2 hours at room temperature.The reaction mixture was extracted two times with dichloromethane (2×100mL). The organic layers were combined and washed with saturated sodiumthiosulfate solution, dried with sodium sulfate and the solvent wasremoved in vacuo to yield (2S,5S)-tert-butyl2-formyl-5-methylpyrrolidine-1-carboxylate (3.9 g, 18.29 mmol, 77%) as aslight colored oil and was used directly in the following step.

(2S,5S)-tert-butyl2-(1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

To a solution of (2S,5S)-tert-butyl2-formyl-5-methylpyrrolidine-1-carboxylate (3.9g, 18.30 mmol) in MeOH(15 mL) and ammonium hydroxide (15 mL, 99.9%), glyoxal (11.7 mL, 40% w/vin water, 102.40 mmol) was added dropwise. The biphasic mixture turnedorange and turbid. The reaction was stirred vigorously overnight at roomtemperature. The solvent was removed in vacuo. The crude mixture wasredissolved in ethyl acetate and washed with water. The aqueous layerwas washed an additional time with ethyl acetate. The organic layerswere combined and washed with brine, dried with sodium sulfate and thesolvent was removed in vacuo. The crude material was purified by columnchromatography 85% to 100% ethyl acetate in hexanes to yield(2S,5S)-tert-butyl2-(1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate as an off whitesolid (3.47 g, 13.8 mmol, 75%). LCMS-ESI⁺: calc'd for C₁₃H₂₁N₃O₂: 251.16(M⁺). Found: 252.20 (M+H⁺).

(2S,5S)-tert-butyl2-(4,5-diiodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

A 500 ml round bottom flask was charged with (2S,5S)-tert-butyl2-(1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (3.47 g, 13.8mmol), iodine (7.7 g, 30.4 mmol) and sodium carbonate (4.54 g, 42.8mmol). Dioxane (70 mL) and water (45 mL) was added to mixture and thereaction was stirred vigorously overnight in the dark. The reaction wasthen partitioned between ethyl acetate and a 10% aqueous solution ofsodium thiosulfate and extracted. The aqueous layer was extracted anadditional time with ethyl acetate. The organic layers were combined,dried with sodium sulfate and the solvent was removed in vacuo. Thecrude material was filtered through a plug of silica with 25% ethylacetate in hexanes to yield (2S,5S)-tert-butyl2-(4,5-diiodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate as awhite solid (4.28 g, 8.50 mmol, 62%). LCMS-ESI⁺: calc'd forC₁₃H₁₉I₂N₃O₂: 502.96 (M⁺). Found: 503.94 (M+H⁺).

(2S,5S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

To a solution of (2S,5S)-tert-butyl2-(4,5-diiodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (4.28g, 8.50 mmol) in ethanol (75 mL) and water (75 mL), sodium thiosulfate(10.72 g, 85.1 mmol) was added and the reaction mixture was stirredvigorously for 1 hour at 100° C., 16 hours at 90° C., and 5 hours at100° C. The reaction mixture was partitioned between ethyl acetate andwater. The aqueous layer was washed additionally with ethyl acetate andthe organic layers were combined. The organic layer was dried withsodium sulfate, concentrated and the crude material was purified bycolumn chromatography to yield (2S,5S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate as a whitesolid (2.34 g, 6.20 mmol, 73%). ¹H NMR (400 MHz, cdcl₃) δ 7.04 (s, 1H),4.89 (dd, 1H), 3.92 (m, 1H), 2.91 (s, 1H), 2.18-2.06 (m, 2H), 1.78 (m,1H), 1.52 (m, 1H), 1.48 (s, 9H), 1.13 (d, 3H).

(2S)-1-[(2S,5S)-2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-2-[(1-methoxyethenyl)amino]-3-methylbutan-1-one

A round bottom flask was charged with (2S,5S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (1.5 g,3.98 mmol) and treated with an excess of hydrochloric acid (100 mL of4.0M in dioxane). The mixture was stirred vigorously for 3 hours inwhich time a precipitate formed and the solvent was removed in vacuo. Toa mixture of the crude intermediate,(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.836 g, 4.77 mmol),HATU (1.81 g, 4.77 mmol) in dichloromethane (25 mL),diisopropylethylamine (3.46 mL, 19.9 mmol) was then added dropwise andwas stirred over night under nitrogen. The reaction mixture waspartitioned ethyl acetate and saturated sodium bicarbonate. The organiclayer was dried with sodium sulfate, the solvent removed in vacuo. Thecrude product was purified by column chromatography to yield(2S)-1-[(2S,5S)-2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-2-[(1-methoxyethenyl)amino]-3-methylbutan-1-oneas a white solid (1.63 g, 3.75 mmol, 94%). LCMS-ESI⁺: calc'd forC₁₅H₂₃IN₄O₃: 434.08 (M⁺). Found: 435.51 (M+H⁺).

Example NP

Methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

The synthesis of this compound was prepared according to the procedureof example LR-1 with the following modification. During the suzukicoupling, methyl(S)-1-((2S,5S)-2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas used in lieu of methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.The crude material was purified by preparative HPLC to provide methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamateas a white solid (17 mg, 0.019 mmol, 17%). ¹H NMR (400 MHz, cd₃od) δ8.63 (s, 1H), 8.19 (d, 1H), 8.04 (m, 1H), 7.87 (m, 2H), 7.66 (m, 2H),7.52-7.39 (m, 6H), 5.50 (m, 2H), 5.32 (s, 2H), 5.16 (m, 1H), 4.12 (m,1H), 3.80 (m, 4H), 3.66 (s, 6H), 3.43 (m, 4H), 3.23 (s, 3H), 2.72-1.99(m, 9H), 1.56 (d, 3H), 1.29 (m, 1H), 0.99 (d, 3H), 0.88 (d, 3H).

Example NQ

Methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

The synthesis of this compound was prepared according to the procedureof example LQ with the following modification. During the Suzukicoupling,(2S)-1-[(2S,5S)-2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-2-[(1-methoxyethenyl)amino]-3-methylbutan-1-onewas used in lieu of(2S)-1-[(2S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-[(1-methoxyethenyl)amino]-3-methylbutan-1-one.The crude material was purified by preparative HPLC to provide methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamateas a white solid (110 mg, 0.131 mmol, 57%). ¹H NMR (400 MHz, cd₃od) δ8.65 (s, 1H), 8.21 (d, 1H), 8.04 (m, 2H), 7.91 (s, 1H), 7.81 (m, 1H),7.67 (m, 2H), 7.46 (m, 6H), 5.59 (s, 1H), 5.50 (dd, 1H), 5.33 (s, 2H),5.22-5.09 (m, 1H), 4.14 (m, 2H), 3.74 (s, 1H), 3.65 (m, 6H), 3.52-3.37(m, 2H), 2.60-1.89 (m, 11H), 1.56 (d, 3H), 1.29 (d, 1H), 0.99 (d, 3H),0.88 (d, 3H).

Example NR

Methyl [(2S)-1-{(2S,5S)-2-[5-(2-{(2S)-1-[(2R)-2-amino-2-phenylacetyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-5-methylpyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate

The synthesis of this compound was prepared according to the procedureof NQ with the following modifications. During the amide coupling,(R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid was used in lieu of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid. This was then treatedwith an excess of hydrochloric acid (15 ml, 4.0 M in Dioxane) for 2hours. The crude product was purified by HPLC to provide methyl[(2S)-1-{(2S,5S)-2-[5-(2-{(2S)-1-[(2R)-2-amino-2-phenylacetyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-5-methylpyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamateas a white solid (153 mg, 0.196 mmol, 74%). ¹H NMR (400 MHz, cd₃od) δ8.63 (s, 1H), 8.20 (d, 1H), 7.99 (m, 1H), 7.93 (m, 2H), 7.80 (m, 2H),7.72-7.64 (m, 211), 7.63-7.52 (m, 5H), 5.52 (dd, 1H), 5.44 (m, 1H), 5.33(s, 2H), 5.21-5.10 (m, 1H), 4.80 (m, 2H), 4.14 (m, 1H), 4.02 (m, 1H),3.75 (s, 1H), 3.67 (s, 3H), 3.12 (dd, 1H), 2.72-2.13 (m, 7H), 2.00 (m,3H), 1.56 (d, 3H), 1.30 (d, 1H), 0.98 (d, 3H), 0.88 (d, 3H).

Example NS

(2S,4S)-tert-Butyl2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatewas synthesized from (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylateand methyl(S)-3-methyl-1-((2S,4S)-4-methyl-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamateusing the same conditions employed in the synthesis of methyl{(2S)-1-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate.

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas synthesized from (2S,4S)-tert-butyl2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylateusing the same methods employed in the synthesis of methyl{(1R)-2-[(2S,4S)-2-[7-(4-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)-1H-naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamatefrom (2S,4S)-tert-butyl2-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate,substituting (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid for(R)-2-(methoxycarbonylamino)-2-phenylacetic acid.

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(cyclobutanecarboxamide)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(98 mg, 0.106 mmol) was dissolved in DCM (2.5 mL) and treated with HCl(4.0 M in dioxane, 0.5 mL). After stirring for 1 h, the reaction mixturewas concentrated under vacuum. The crude residue was treated withcyclobutanecarboxylic acid (0.051 mL, 0.53 mmol), HATU (48 mg, 0.13mmol), DMF (2 mL) and DIPEA (0.185 mL, 1.06 mmol). After stirring at RTfor 20 min, the reaction was quenched with water and the mixture waspurified by reverse-phase HPLC to afford methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(cyclobutanecarboxamide)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(87 mg). MS (ESI) m/z 904 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.62 (d,J=8.5 Hz, 1H), 8.40 (d, J=12.4 Hz, 3H), 8.10 (d, J=6.5 Hz, 2H), 8.01 (d,J=9.0 Hz, 2H), 7.71 (d, J=8.9 Hz, 2H), 7.53 (dd, J=7.8, 1.4 Hz, 2H),7.50-7.40 (m, 3H), 5.68 (s, 1H), 5.61 (t, J=8.2 Hz, 1H), 5.43 (dd,J=10.9, 7.0 Hz, 1H), 4.41 (t, J=8.5 Hz, 1H), 4.35 (d, J=7.0 Hz, 1H),3.92 (t, J=9.5 Hz, 1H), 3.81 (dd, J=21.9, 12.1 Hz, 1H), 3.68 (s, 3H),3.61 (t, J=10.5 Hz, 1H), 3.44 (qd, J=9.6, 5.4 Hz, 2H), 3.27-3.11 (m,4H), 2.78 (dt, J=12.5, 7.8 Hz, 2H), 2.64 (td, J=12.6, 6.5 Hz, 2H),2.45-2.27 (m, 1H), 2.26-1.85 (m, 8H), 1.86-1.71 (m, 1H), 1.29 (d, J=6.3Hz, 4H), 1.07-0.80 (m, 7H).

Example NT

methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(3,3-difluorocyclobutanecarboxamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(3,3-difluorocyclobutanecarboxamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas synthesized from methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateusing the same methods employed in the synthesis of methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(cyclobutanecarboxamide)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting 3,3-difluorocyclobutanecarboxylic acid forcyclobutanecarboxylic acid. MS (ESI) m/z 940 [M+H]⁺.

Example NU

methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas synthesized from methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateusing the same methods employed in the synthesis of methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(cyclobutanecarboxamide)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,omitting the final HATU coupling step. MS (ESI) m/z 821 [M+H]⁺.

Example NV

methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(2-methoxyacetamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(2-methoxyacetamido)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas synthesized from methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateusing the same methods employed in the synthesis of methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-(cyclobutanecarboxamide)-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting 2-methoxyacetic acid for cyclobutanecarboxylic acid. MS(ESI) m/z 894 [M+H]⁺.

Example NW

methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas synthesized from (2S,4S)-tert-butyl2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylateusing the same method employed in the synthesis of methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (R)-2-(methoxycarbonylamino)-2-phenylacetic acid for(R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid. MS (ESI) m/z 880[M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.31 (dd, J=21.3, 7.6 Hz, 4H), 7.96(d, J=8.4 Hz, 2H), 7.88 (dd, J=8.7, 3.3 Hz, 2H), 7.66-7.54 (m, 2H), 7.46(ddd, J=21.7, 14.4, 6.9 Hz, 4H), 5.62-5.49 (m, 2H), 5.43 (dd, J=10.8,7.1 Hz, 1H), 4.54-4.18 (m, 2H), 3.88 (t, J=9.8 Hz, 1H), 3.77 (dd,J=22.6, 13.3 Hz, 1H), 3.73-3.54 (m, 6H), 3.46 (ddd, J=15.6, 9.6, 5.5 Hz,2H), 3.36-3.29 (m, 1H), 2.73 (dd, J=12.5, 6.7 Hz, 2H), 2.67-2.49 (m,2H), 2.30-2.11 (m, 2H), 2.09-1.94 (m, 1H), 1.36-1.17 (m, 4H), 1.10-0.83(m, 6H).

Example NX

methyl(S)-1-((2S,5S)-2-(2′-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,5S)-2-(2′-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas synthesized according to the method described for the synthesis ofmethyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting methyl(S)-3-methyl-1-((2S,5S)-2-methyl-5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamatefor methyl(S)-3-methyl-1-((2S,4S)-4-methyl-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate.MS (ESI) m/z 880 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.58-8.52 (m, 1H),8.47 (d, J=9.5 Hz, 2H), 8.27 (d, J=8.3 Hz, 1H), 8.17 (dd, J=19.0, 10.0Hz, 2H), 8.09 (t, J=9.9 Hz, 1H), 7.82 (ddd, J=26.2, 18.1, 8.9 Hz, 2H),7.45 (tt, J=13.5, 6.9 Hz, 5H), 5.56 (d, J=8.5 Hz, 2H), 5.37 (dd, J=10.7,7.0 Hz, 1H), 4.23 (dd, J=23.8, 8.5 Hz, 1H), 3.88 (t, J=9.7 Hz, 1H),3.82-3.65 (m, 4H), 3.62 (s, 3H), 3.54-3.38 (m, 2H), 3.35 (s, 1H), 3.26(s, 3H), 2.80 (ddd, J=25.6, 20.1, 6.8 Hz, 1H), 2.68-2.27 (m, 4H),2.24-1.89 (m, 3H), 1.67 (d, J=6.6 Hz, 2H), 1.32 (d, J=6.2 Hz, 1H),1.20-1.02 (m, 1H), 0.94 (dd, J=26.4, 6.7 Hz, 5H).

Example NY

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(2S,4S)-tert-Butyl2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(120 mg, 0.152 mmol) was dissolved in DCM (5 mL) and treated with HCl(4.0 mL in dioxane, 1 mL). After stirring for 1 h, the reaction mixturewas concentrated under reduced pressure. The crude residue was treatedwith (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (35 mg,0.18 mmol), HATU (69 mg, 0.18 mmol), DMF (1 mL) and DIPEA (0.26 mL, 1.5mmol). After 20 min, the reaction was quenched with water. The productwas purified by reverse-phase HPLC to afford methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(120 mg). MS (ESI) m/z 862 [M+H]⁺.

Example NZ

methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((S)-2-methoxycarbonylamino-2-(tetrahydro-2H-pyran-4-yl)acetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas prepared using a method analogous to that employed in the synthesisof methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. MS (ESI) m/z888 [M+H]⁺.

Example OA

4-Bromo-3-(difluoromethoxy)benzoic acid

Methyl 4-bromo-3-hydroxybenzoate (2.31 g, 10 mmol), sodium2,2-dichloro-2-fluoroacetate (4.57 g, 30 mmol) and Cs₂CO₃ (4.89 g, 15mmol) were combined in DMF (50 mL). The stirred reaction mixture washeated to 80° C. for 22 h then cooled to RT. The reaction mixture wasdiluted with EtOAc and washed with water, saturated aqueous NaHCO₃ andbrine, then dried over MgSO₄, filtered and concentrated. The cruderesidue was purified by silica column chromatography (0% to 20%EtOAc/Hex) to afford the difluoromethyl ether (1.87 g, 67%). Thepurified material was dissolved in MeOH (40 mL) and treated with LiOH(1.0 M in water, 10 mL). The reaction mixture was stirred at RT for 3d,then concentrated underreduced pressure to remove most of the MeOH. Theaqueous solution was then poured into a separatory funnel containingwater. The solution was acidified to pH 1-2 with 10% HCl, then extracted3× with DCM. The combined organic fractions were dried over MgSO₄,filtered and concentrated to provide 4-bromo-3-(difluoromethoxy)benzoicacid (yield undetermined, material carried on crude assuming totalconversion).

2-Bromo-1-(4-bromo-3-(difluoromethoxy)phenyl)ethanone

4-Bromo-3-(difluoromethoxy)benzoic acid (6.65 mmol) was suspended in DCM(33 mL) and thionyl chloride (2.9 mL, 33 mmol) was added, followed byDMF (5 drops). After stirring at RT for 2 h, the reaction mixture wasconcentrated under reduced pressure. The crude residue was dissolved inDCM (17 mL) and treated with TMS-diazomethane (2.0 M in hexane, 8.3 mL,16.6 mmol). After stirring at RT for 2 h, HBr (33% w/w in AcOH) (5.8 mL,33 mmol) was added dropwise. After stirring for 1 h more at RT, thereaction mixture was concentrated under reduced pressure. The cruderesidue was diluted with EtOAc. The organic solution was washed withsaturated aqueous NaHCO₃ and brine, then dried over MgSO₄, filtered andconcentrated to afford2-Bromo-1-(4-bromo-3-(difluoromethoxy)phenyl)ethanone (yieldundetermined, material carried on crude assuming total conversion).

(S)-2-(2-(4-Bromo-3-(difluoromethoxy)phenyl)-2-oxoethyl) 1-tert-butylpyrrolidine-1,2-dicarboxylate

2-Bromo-1-(4-bromo-3-(difluoromethoxy)phenyl)ethanone (6.65 mmol) andBoc-proline (1.72 g, 7.98 mmol) were suspended in MeCN (13 mL) andtriethylamine (1.00 mL, 7.32 mmol) was added. The reaction mixture wasstirred at RT for 14 h, then diluted with EtOAc. The organic solutionwas washed with water saturated aqueous NaHCO₃ and brine, then driedover MgSO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography (19% to 40%EtOAc/Hex) to afford(S)-2-(2-(4-bromo-3-(difluoromethoxy)phenyl)-2-oxoethyl) 1-tert-butylpyrrolidine-1,2-dicarboxylate (2.48 g, 78% over 4 steps).

(S)-tert-Butyl2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-2-(2-(4-Bromo-3-(difluoromethoxy)phenyl)-2-oxoethyl) 1-tert-butylpyrrolidine-1,2-dicarboxylate (2.48 g, 5.19 mmol) and NH₄OAc (8.00 g,104 mmol) were combined in PhMe. The stirred reaction mixture was heatedto 100° C. for 3 h 20 min then cooled to RT and diluted with EtOAc. Theorganic solution was washed with water saturated aqueous NaHCO₃ 3× thendried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (45% to 75%EtOAc/Hex) to afford (S)-tert-butyl2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(1.51 g, 63%).

Methyl(S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-tert-Butyl2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(400 mg, 0.873 mmol) was dissolved in DCM (10 mL) and treated with HCl(4.0 M in dioxane, 2 mL). The reaction mixture was stirred at RT for 50min, then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (168 mg,0.960 mmol), HATU (365 mg, 0.960 mmol) and DMF (4 mL) then cooled to 0°C. DIPEA (0.760 mL, 4.37 mmol) was added dropwise and the reactionmixture was stirred for 30 min. After warming to RT, the mixture wasdiluted with EtOAc and the organic solution was washed with saturatedaqueous NaHCO₃, and brine then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (0% to 33% MeOH/EtOAc) to afford methyl(S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(333 mg, 74%).

(2S,4S)-tert-Butyl4-(methoxymethyl)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylatewas prepared according to the method utilized in the synthesis of methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate,substituting (2S,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatefor methyl(S)-1-((S)-2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.

(2S,4S)-tert-Butyl2-(7-(2-(difluoromethoxy)-4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatewas prepared from methyl(S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateand (2S,4S)-tert-butyl4-(methoxymethyl)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylateusing the same conditions employed in the synthesis of methyl{(2S)-1-[(2S,4S)-2-{2′-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate.

Methyl(R)-1-((S)-2-(5-(4-(2-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas prepared according to the method employed in the synthesis of methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (2S,4S)-tert-butyl2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatewith (2S,4S)-tert-butyl2-(7-(2-(difluoromethoxy)-4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylateand (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid with(R)-2-(methoxycarbonylamino)-2-phenylacetic acid. MS (ESI) m/z 907[M+H]⁺.

Example OB

methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas prepared using a method analogous to that employed in the synthesisof methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[12-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid for(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. MS (ESI) m/z846 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.51 (s, 2H), 8.45 (d, J=8.6 Hz,2H), 8.17 (d, J=8.5 Hz, 2H), 8.10 (d, J=9.0 Hz, 2H), 7.76 (d, J=8.9 Hz,2H), 5.43 (td, J=11.4, 7.2 Hz, 2H), 4.40 (s, 2H), 4.29 (d, J=7.1 Hz,2H), 3.91-3.72 (m, 1H), 3.73-3.47 (m, 8H), 3.41 (d, J=9.4 Hz, 3H), 3.35(s, 1H), 2.87 (d, J=5.8 Hz, 1H), 2.76 (tt, J=13.0, 6.6 Hz, 2H), 2.63 (d,J=5.6 Hz, 1H), 2.30-2.13 (m, 1H), 2.13-1.92 (m, 3H), 1.41-1.20 (m, 3H),1.08-0.90 (m, 6H), 0.87 (d, J=6.6 Hz, 6H).

Example OC

(S)-tert-Butyl2-(7-bromo-5-iodo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

(S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(0.990 g, 2.38 mmol) was suspended in DMF (8 mL) and treated with NIS(1.03 g, 4.59 mmol). The reaction mixture was stirred at 70° C. for 2d,then cooled to RT. The mixture was then diluted with EtOAc and theorganic solution was washed with 3× with brine then dried over MgSO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (30% to 55% EtOAc/Hex) toafford (S)-tert-butyl2-(7-bromo-5-iodo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(753 mg, 58%).

(S)-tert-Butyl2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate

In a screw-top glass tube capped with a rubber septum, (S)-tert-Butyl2-(7-bromo-5-iodo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(524 mg, 1.00 mmol) was dissolved in a solution of MeCN (4 mL) andtriethylamine (1 mL) and cooled to 0° C. Propyne gas was bubbled throughthe solution for 10 min and the vessel was charged with Pd(PPh₃)Cl₂ (70mg, 0.10 mmol) and CuI (57 mg, 0.30 mmol). Propyne was bubbled throughthe suspension for another 7 min and the tube was sealed with a Teflonscrew cap. The reaction mixture was warmed to RT and stirred for 2 hafter which the tube was carefully opened to air, allowing the propyneto bubble out of solution. The contents of the tube were filtered overcelite and rinsed with EtOAc then concentrated under reduced pressure.The crude residue was purified by silica column chromatography (40% to65% EtOAc/Hex) to afford (S)-tert-butyl2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(415 mg, 91%).

Methyl(S)-1-((S)-2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas prepared according to the procedure described for the synthesis ofmethyl(S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (S)-tert-butyl2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylatefor (S)-tert-Butyl2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.

Methyl(R)-2-((2S,4S)-2-(2′-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-5′-(prop-1-ynyl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamatewas prepared according to the method employed in the synthesis of methyl(R)-1-((S)-2-(5-(4-(2-((2S,4S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting methyl(S)-1-((S)-2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatefor methyl(S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.MS (ESI) m/z 904 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.56 (s, 1H),8.38-8.28 (m, 1H), 8.22 (dd, J=22.7, 16.8 Hz, 2H), 8.02-7.84 (m, 3H),7.64 (d, J=12.9 Hz, 2H), 7.56-7.36 (m, 5H), 5.62-5.50 (m, 2H), 5.45 (t,J=7.6 Hz, 1H), 4.37 (t, J=11.2 Hz, 1H), 4.23 (s, 1H), 4.06 (dd, J=30.6,23.2 Hz, 1H), 3.88 (t, J=9.8 Hz, 1H), 3.79 (t, J=8.8 Hz, 1H), 3.70 (s,3H), 3.65-3.56 (m, 3H), 3.54-3.38 (m, 2H), 3.30-3.26 (m, 3H), 2.85-2.70(m, 1H), 2.62 (dd, J=27.6, 22.5 Hz, 2H), 2.48-1.99 (m, 8H), 1.17-0.82(m, 6H).

Example OD

(2S,4S)-tert-Butyl2-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-5′-(prop-1-ynyl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatewas prepared according to the method described for the synthesis of(2S,4S)-tert-butyl2-(7-(2-(difluoromethoxy)-4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate,replacing methyl(S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewith methyl(S)-1-((S)-2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.

Methyl(S)-1-((S)-2-(2′-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-5-(prop-1-ynyl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewas prepared according to the method described for the synthesis ofmethyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (2S,4S)-tert-butyl2-(2′-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-5′-(prop-1-ynyl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatefor (2S,4S)-tert-butyl2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 844 [M+H]⁺.

Example OE

(2S,5S)-Ethyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate

(2S,5S)-Ethyl 5-methylpyrrolidine-2-carboxylate-TFA (10.0 g, 39.3 mmol),(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (6.88 g, 39.3 mmol)and HATU (14.9 g, 39.3 mmol) were combined in DMF (100 mL) and DIPEA(15.0 mL, 86.5 mmol) was added. After stirring for 1 h at RT, thereaction mixture was diluted with EtOAc. The organic phase was washedsuccessively with 10% HCl, saturated aqueous NaHCO₃ and brine, thendried over MgSO₄, filtered and concentrated under reduced pressure toafford (2S,5S)-ethyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate.The crude material was carried on without further purification.

(2S,5S)-1-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid

(2S,5S)-Ethyl1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate(39.3 mmol, assuming complete conversion from the previoustransformation) was suspended in MeOH (200 mL) and aqueous LiOH (1.0 M,100 mL, 100 mmol) was added. The reaction mixture was stirred o/n, thenconcentrated under reduced pressure to remove most of the MeOH. Theaqueous solution was washed 2× with DCM before being acidified to pH-1-2with 10% HCl. The acidic aqueous phase was then extracted 5× with EtOAc.The combined EtOAc extracts were dried over MgSO₄ filtered andconcentrated under reduced pressure to afford(2S,5S)-1-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid (6.89 g, 56% over 2 steps).

Example OF

3-Vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one

A 3-neck oven-dried 500 mL round-bottom flask was cooled under Ar, thencharged with 3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one(12.0 g, 42.1 mmol), potassium vinyltrifluoroborate (8.47 g, 6.32 mmol),Pd(OAc)₂ (473 mg, 2.11 mmol), SPhos (1.74 g, 4.25 mmol), K₂CO₃ (17.5 g,126 mmol) and anhydrous propanol (120 mL). The reaction mixture wassparged with Ar for 16 min, then heated to reflux for 5.5 h. Uponcompletion, the reaction mixture was cooled to RT and concentrated underreduced pressure. The crude residue was suspended in DCM, then washedwith H₂O and brine. The organic solution was dried over MgSO₄, filteredand concentrated under reduced pressure. The resulting residue wasfurther purified via silica plug, eluting with DCM to afford3-vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (10.2 g, 87%).

3-(2-Bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one

3-Vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (9.98 g, 36.1mmol) was dissolved in a stirred solution of THF (70 mL), DMSO (70 mL)and H₂O (35 mL). NBS (6.75 g, 37.9 mmol) was added in a single portionand the reaction mixture was stirred at RT for 33 min. Upon completion,the reaction medium was diluted with EtOAc and washed twice with H₂O andonce with brine. The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure. The resulting crude bromohydrin wassuspended in DCM (200 mL) and treated with activated MnO₂ (62.7 g, 722mmol). After stirring for 15 h at RT, the reaction mixture was filteredover celite and the filter cake was rinsed several times with DCM. Thecombined filtrate (˜400 mL) was treated with MeOH (˜100 mL) and themixture was gradually concentrated under reduced pressure, causing solidmaterial to precipitate from solution. When the liquid volume reached˜200 mL, the solid was filtered off and rinsed with MeOH. Theconcentration/precipitation/filtration/rinsing sequence was performed 2×more, resulting in the collection of 3 crops of powdered3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.49g, 56% over 2 steps).

(4S)-1-tert-Butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate

3-(2-Bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.47g, 20.1 mmol) and(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (5.22 g, 20.1 mmol) were suspended in 2-Me-THF (75 mL) and treatedwith Cs₂CO₃ (3.27 g, 10.1 mmol). After stirring 4 h at RT, the reactionmixture was diluted with diluted with DCM. The organic layer was washedwith H₂O. The aqueous layer was then back extracted 2× with DCM. Thecombined organics were dried over MgSO₄, filtered and concentrated underreduced pressure. The crude residue was purified by silica columnchromatography (10% to 50% EtOAc/DCM) to afford (4S)-1-tert-butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.73 g, 70%).

(2S,4S)-2-(2-(9-Bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate

(4S)-1-tert-Butyl2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl)4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.66 g, 13.9 mmol) wasdissolved in a solution of DCM (100 mL) and MeOH (40 mL), then treatedwith pyridinium tribromide (4.90 g, 15.3 mmol). After stirring at RT for1.75 h, the reaction mixture was diluted with DCM and washedsuccessively with 10% HCl, saturated aqueous NaHCO₃ and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated underreduced pressure and the crude material was carried on without furtherpurification.

(2R,4R)-1-tert-Butyl2-(2-(9-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate

(2S,4S)-2-(2-(9-Bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (8.76 g,13.94 mmol) was treated with a solution of(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid (6.85 g, 23.92 mmol) in 2-Me-THF (70 mL) and Cs₂CO₃ (3.63 g, 11.15mmol). The stirred reaction mixture was heated to 50° C. for 20 h, thencooled to RT and diluted with EtOAc. The organic phase was washed withH₂O and brine, then dried over MgSO₄, filtered and concentrated underreduced pressure. The crude residue was purified by silica columnchromatography (0% to 30% MeOH/EtOAc) to afford (2R,4R)-1-tert-butyl2-(2-(9-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (10.47 g, 90%).

tert-Butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

(2R,4R)-1-tert-Butyl2-(2-(9-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carbonyloxy)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (10.47 g, 12.56 mmol) andNH₄OAc (50.9 g, 660 mmol) were suspended in a solution of 10:1PhMe/2-methoxyethanol (132 mL). The stirred reaction mixture was heatedto 110° C. for 4.5 h, then cooled to RT and diluted with EtOAc. Theorganic phase was washed 3× with saturated aqueous NaHCO₃, then driedover MgSO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica column chromatography (0% to 30%MeOH/EtOAc) to afford tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(8.33 g, 84%).

tert-Butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

tert-Butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(8.33 g, 1.049 mmol) was suspended in DCM and activated MnO₂ (55.0 g,630 mmol) was added in a single portion. After 13 h, MeOH (200 mL) wasadded and the slurry was filtered over celite. The filter cake waswashed with MeOH (600 mL) and the filtrate was concentrated underreduced pressure. The crude material was purified by silica columnchromatography (0% to 45% MeOH/EtOAc) to afford tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(4.85 g, 58%).

Methyl{(2S,3S)-1-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate

tert-Butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(179 mg, 0.226 mmol) was dissolved in DCM (4 mL) and HCl (4.0 M indioxane, 1 mL) was added. The reaction mixture was stirred for 1 h at RTthen concentrated under reduced pressure. The resulting residue wastreated with (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (51mg, 0.27 mmol), HATU (95 mg, 0.25 mmol), DMF (2 mL) and DIPEA (0.39 mL,2.3 mmol). After stirring for 6 min, the reaction was quenched with H₂O,filtered and purified by reverse phase HPLC to afford methyl{(2S,3S)-1-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate(116 mg, 59%). MS (ESI) m/z 864 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.57(d, J=14.7 Hz, 1H), 8.45 (s, 1H), 8.20 (d, J=14.4 Hz, 1H), 8.15-7.98 (m,2H), 7.91 (dd, J=21.8, 14.1 Hz, 2H), 7.85-7.69 (m, 2H), 7.69-7.48 (m,2H), 5.42-5.12 (m, 5H), 4.34 (dd, J=22.3, 13.7 Hz, 1H), 4.30-4.10 (m,2H), 3.87-3.73 (m, 1H), 3.73-3.63 (m, 7H), 3.62-3.48 (m, 2H), 3.48-3.38(m, 4H), 3.35 (s, 3H), 2.95-2.70 (m, 1H), 2.70-2.55 (m, 2H), 2.55-2.20(m, 2H), 2.20-1.91 (m, 3H), 1.77 (d, J=42.0 Hz, 1H), 1.65 (d, J=6.6 Hz,3H), 1.43 (t, J=24.6 Hz, 1H), 1.28 (d, J=6.2 Hz, 1H), 1.23-1.01 (m, 3H),0.98 (d, J=6.6 Hz, 3H), 0.90 (dd, J=13.1, 5.9 Hz, 10H).

Example OG

Methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-1-alloisoleucyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamatewas prepared from tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylateby the same method employed in the synthesis of{(2S,3S)-1-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate,replacing (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid with(2S,3R)-2-(methoxycarbonylamino)-3-methylpentanoic acid. MS (ESI) m/z864 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.62-8.41 (m, 1H), 8.22 (s, 1H),8.07 (dt, J=20.1, 10.0 Hz, 1H), 7.89 (dt, J=35.6, 15.6 Hz, 2H), 7.77(dd, J=20.3, 7.0 Hz, 2H), 7.68-7.48 (m, 2H), 5.95 (d, J=5.0 Hz, 1H),5.42-5.13 (m, 4H), 4.47 (t, J=5.5 Hz, 1H), 4.40-4.09 (m, 2H), 3.80-3.73(m, 1H), 3.73-3.62 (m, 6H), 3.57 (dt, J=16.1, 9.7 Hz, 2H), 3.40 (s, 3H),3.34 (d, J=7.5 Hz, 1H), 2.81 (dd, J=18.4, 12.5 Hz, 1H), 2.63 (td,J=13.3, 6.8 Hz, 2H), 2.55-2.18 (m, 2H), 2.16-1.77 (m, 4H), 1.65 (d,J=6.6 Hz, 3H), 1.50-1.31 (m, 1H), 1.26 (dd, J=15.6, 6.7 Hz, 2H),1.17-1.03 (m, 2H), 0.98 (dd, J=6.7, 4.5 Hz, 5H), 0.89 (dd, J=15.5, 7.8Hz, 3H), 0.86-0.74 (m, 3H).

Example OH

Methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

tert-Butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(102 mg, 0.128 mmol) was dissolved in DCM (4 mL) and HCl (4.0 M indioxane, 2.0 mL, 8.0 mmol) was added. After stirring at RT for 30 min,the solution was concentrated under reduced pressure. The residue wastreated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (29 mg,0.141 mmol), COMU (60 mg, 0.141 mmol), DMF (3.0 mL) and DIPEA (0.223 mL,1.28 mmol). After stirring at RT for 20 min, the reaction mixture wasdiluted with EtOAc. The organic solution was washed with saturatedaqueous NaHCO₃ and brine, then dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified byreverse-phase HPLC to afford methyl{(IR)-2-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamateas the bis-TFA salt (82.4 mg, 60%). MS (ESI) m/z 866 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 7.94-7.67 (m, 4H), 7.59 (d, J=9.1 Hz, 1H), 7.52 (s, 1H),7.48-7.33 (m, 4H), 7.11 (d, J=18.7 Hz, 1H), 5.68 (d, J=6.3 Hz, 1H),5.48-5.33 (m, 1H), 5.23 (dd, J=24.1, 15.7 Hz, 1H), 5.17-5.03 (m, 3H),4.22 (dd, J=17.0, 9.6 Hz, 1H), 4.16-4.01 (m, 1H), 3.91 (d, J=24.1 Hz,1H), 3.83-3.68 (m, 1H), 3.68-3.59 (m, 3H), 3.59-3.49 (m, 3H), 3.38 (ddd,J=15.9, 9.6, 5.7 Hz, 2H), 3.28-3.14 (m, 5H), 3.10 (dd, J=14.0, 8.2 Hz,1H), 3.00 (dd, J=17.8, 9.6 Hz, 1H), 2.92 (dd, J=14.5, 6.7 Hz, 1H),2.73-2.41 (m, 2H), 2.40-2.11 (m, 2H), 2.11-1.83 (m, 2H), 1.54 (t, J=9.7Hz, 2H), 1.24 (d, J=6.2 Hz, 1H), 1.06 (t, J=8.0 Hz, 1H), 0.99 (d, J=6.8Hz, 1H), 0.94 (d, J=6.6 Hz, 2H), 0.85 (d, J=6.7 Hz, 2H).

Example OI

tert-Butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatewas prepared from(2S,4S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate by the samemethod employed in the synthesis of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate,replacing(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid with(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid.

Methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

tert-Butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(137 mg, 0.179 mmol) was dissolved in DCM (5 mL) and HCl (4.0 M indioxane, 1 mL) was added. After stirring at RT for 1.5 h, the reactionmixture was concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (69 mg,0.39 mmol), HATU (149 mg, 0.393 mmol), DMF (2.0 mL) and DIPEA (0.31 mL,1.8 mmol). After stirring for 15 min at RT, the reaction mixture wasquenched with water and purified by HPLC to provide methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(123 mg). MS (ESI) m/z 880 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.48 (s,1H), 8.05 (t, J=11.2 Hz, 1H), 7.92 (dd, J=19.7, 10.1 Hz, 2H), 7.74 (s,2H), 7.59-7.44 (m, 2H), 5.49 (s, 1H), 5.40 (dt, J=16.3, 8.1 Hz, 1H),5.31-5.15 (m, 3H), 4.47-4.10 (m, 4H), 3.86-3.44 (m, 12H), 3.39 (dd,J=13.2, 7.1 Hz, 6H), 2.94-2.57 (m, 4H), 2.25-1.94 (m, 4H), 1.02-0.82 (m,12H).

Example OJ

Methyl{(2S,3S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamatewas prepared from tert-Butyl(2S,4S)-2-(5-{2-[(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylateusing the same method employed in the synthesis of methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate,replacing with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid with(2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid. MS (ESI) m/z908 [M+H]⁺.

Example OK

tert-Butyl(2S,4S)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatewas synthesized from(2S,4S)-2-(2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl)1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate using thesame methods described for the synthesis of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate,substituting(S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylicacid for(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid.

Methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamatewas synthesized from tert-butyl(2S,4S)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylateusing the same method employed for the synthesis of methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamatesubstituting tert-butyl(2S,4S)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatefor tert-Butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 871 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 7.87 (ddd, J=20.5,15.3, 6.8 Hz, 4H), 7.65 (s, 1H), 7.50-7.38 (m, 5H), 7.17 (s, 1H), 5.41(d, J=24.5 Hz, 1H), 5.28 (t, J=8.3 Hz, 1H), 5.20 (d, J=7.3 Hz, 3H), 4.24(d, J=7.2 Hz, 1H), 4.12 (d, J=10.3 Hz, 1H), 4.03-3.94 (m, 1H), 3.89 (dd,J=15.4, 8.6 Hz, 1H), 3.77 (t, J=9.6 Hz, 1H), 3.72-3.64 (m, 4H),3.63-3.52 (m, 4H), 3.43 (qd, J=9.5, 5.6 Hz, 3H), 3.30 (s, 3H), 3.24-3.08(m, 2H), 2.97 (dd, J=11.6, 5.4 Hz, 2H), 2.59 (dt, J=21.1, 7.8 Hz, 3H),2.29 (s, 1H), 2.24-2.14 (m, 2H), 2.11-1.85 (m, 2H), 0.92 (dd, J=15.8,6.7 Hz, 6H).

Example OL

tert-Butyl(2S,4S)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatewas prepared according to the method described for the synthesis oftert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate,substituting tert-butyl(2S,4S)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno-[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatefor tert-Butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.

Methyl{(2S)-1-[(2S)-2-(9-{2-[(2S,4S)-1-[(2R)-2-amino-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamatewas prepared according to the method described for the synthesis ofmethyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-tert-butoxycarbonylamino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamatewith tert-butyl(2S,4S)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 811 [M+H]⁺.

Example OM

tert-Butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-1-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatewas synthesized from3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, by thesame methods employed in the synthesis of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate,substituting(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid for(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid and(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid for(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-carboxylicacid.

tert-Butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatewas prepared according to the method described for the synthesis oftert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate,substituting tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatefor tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.

Methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S,3R)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamatewas prepared from tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylateaccording to the same method described for the synthesis of methyl(S)-1-((2S,4S)-2-(2′-((2S,4S)-1-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting (2S,4S)-tert-Butyl2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatewith tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 866 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.44 (d, J=19.8 Hz,1H), 8.02 (t, J=8.6 Hz, 2H), 7.98-7.81 (m, 3H), 7.74 (dd, J=22.2, 13.6Hz, 2H), 7.63-7.41 (m, 2H), 5.79 (d, J=6.0 Hz, 1H), 5.42 (dt, J=43.3,21.5 Hz, 2H), 5.31-5.10 (m, 5H), 4.85-4.70 (m, 1H), 4.52 (d, J=3.8 Hz,1H), 4.31 (t, J=8.2 Hz, 1H), 4.17 (dd, J=20.8, 8.8 Hz, 1H), 3.80 (dt,J=19.0, 7.3 Hz, 2H), 3.73-3.63 (m, 7H), 3.63-3.49 (m, 3H), 3.39 (d,J=9.7 Hz, 4H), 3.35 (s, 5H), 3.28 (d, J=4.4 Hz, 3H), 2.84 (d, J=8.8 Hz,1H), 2.72 (dd, J=12.5, 6.6 Hz, 1H), 2.59-2.45 (m, 1H), 2.45-2.11 (m,4H), 2.11-1.82 (m, 2H), 1.56 (d, J=6.6 Hz, 3H), 1.35-1.21 (m, 1H),1.22-1.12 (m, 4H), 1.10-1.01 (m, 2H), 0.99 (d, J=6.6 Hz, 3H), 0.91 (d,0.1=6.7 Hz, 3H).

Example ON

methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-(methoxymethyl)-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-(methoxymethyl)-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamatewas prepared according to the method described for the synthesis ofmethyl{(2S,3S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamatesubstituting tert-butyl(2S,4S)-2-[9-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatefor tert-Butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 863 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.43 (d, J=24.6 Hz,1H), 8.01 (dt, J=16.1, 8.0 Hz, 1H), 7.95-7.78 (m, 2H), 7.77-7.64 (m,2H), 7.59-7.41 (m, 2H), 5.79 (d, J=5.8 Hz, 1H), 5.39 (dt, J=46.2, 23.1Hz, 1H), 5.27-5.07 (m, 3H), 4.85-4.72 (m, 1H), 4.42 (t, J=8.6 Hz, 1H),4.31 (d, J=7.9 Hz, 1H), 4.17 (dd, J=19.7, 8.7 Hz, 1H), 3.81 (dd, J=23.6,13.3 Hz, 1H), 3.69 (d, J=10.0 Hz, 5H), 3.60 (dd, J=14.7, 7.8 Hz, 2H),3.42 (s, 3H), 3.17 (d, J=6.1 Hz, 1H), 3.07 (s, 1H), 2.99-2.91 (m, 1H),2.85 (s, 1H), 2.73 (dd, J=12.5, 6.4 Hz, 1H), 2.62-2.48 (m, 1H),2.45-2.14 (m, 3H), 2.10-1.91 (m, 2H), 1.83 (s, 1H), 1.57 (d, J=6.6 Hz,3H), 1.44 (d, J=7.4 Hz, 1H), 1.34-1.23 (m, 1H), 1.20-0.96 (m, 5H), 0.90(dt, J=14.8, 6.7 Hz, 9H).

Example OO

Methyl{(2S)-1-[(2S)-2-(5-{2-[(2S,4S)-1-[(2R)-2-amino-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamatewas prepared according to the method described for the synthesis ofmethyl (S)-1((2S,4S)-2-(2′-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate,substituting tert-butyl(2S,4S)-2-[9-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatefor (2S,4S)-tert-butyl2-(2′-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-methylpyrrolidin-2-yl)1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-carboxylate.MS (ESI) m/z 811 [M+H]⁺.

Example OP

Methyl {(1R)-2-[(2S,4S)-2-(9-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamatewas synthesized according to the protocol described for the preparationof methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}-carbamate,substituting tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho-[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatefor tert-butyl(2S,4S)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,4,5,11tetrahydroisochromeno-[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 886 [M+H]⁺. 1H NMR (400 MHz, cd₃od) δ 8.02-7.85 (m, 2H),7.85-7.68 (m, 2H), 7.58 (d, J=21.5 Hz, 1H), 7.55-7.35 (m, 4H), 7.31 (d,J=13.6 Hz, 1H), 5.43 (d, J=19.1 Hz, 1H), 5.28 (t, J=8.3 Hz, 1H),5.25-5.10 (m, 3H), 4.13 (t, J=9.5 Hz, 1H), 3.93-3.54 (m, 7H), 3.42 (qd,J=9.5, 5.5 Hz, 2H), 3.34 (d, J=7.9 Hz, 1H), 3.28 (s, 3H), 3.19 (t, J=7.8Hz, 2H), 3.00 (t, J=7.8 Hz, 2H), 2.74-2.46 (m, 3H), 2.44-2.15 (m, 2H),2.12-1.86 (m, 2H), 1.56 (d, J-6.7 Hz, 2H), 1.29 (d, J=6.3 Hz, 1H),1.15-1.01 (m, 1H), 0.98 (d, J=6.7 Hz, 2H), 0.88 (d, J=6.8 Hz, 2H).

Example OQ

(2S,4S)-1-Tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-ethoxypyrrolidine-1,2-dicarboxylate

To a slurry of9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.50 g,6.8 mmol) in MeCN (20 mL) was added(2S,4S)-1-(tert-butoxycarbonyl)-4-ethoxypyrrolidine-2-carboxylic acid(2.68 g, 10.3 mmol) and DIPEA (1.3 mL, 7.5 mmol). The reaction washeated with stirring to 50° C. for 18 h. The reaction was then cooled toroom temperature and diluted with EtOAc. The solution was washed withHCl (1N) and brine. The aqueous layers were backextracted with EtOAc andthe resulting organic layers were combined, dried (Na₂SO₄) andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (15% to 50% EtOAc/Hexanes) to afford(2S,4S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-ethoxypyrrolidine-1,2-dicarboxylate (2.08 g, 56%).

Tert-butyl(2S,4S)-2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate

To a solution of (2S,4S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)4-ethoxypyrrolidine-1,2-dicarboxylate (2.08 g, 3.8 mmol) in a mixture oftoluene (30 mL) and methoxyethanol (4 mL) was added ammonium acetate(2.90 g, 37.7 mmol). The solution was heated with stirring to 80° C. for18 h. The reaction was then cooled to room temperature and diluted withEtOAc. The solution was washed with brine, and the resulting aqueouslayer was backextracted with EtOAc. The resulting organic layers werecombined, dried (Na₂SO₄), and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (10% to 75%EtOAc(w/5% MeOH)/Hexanes) to afford tert-butyl(2S,4S)-2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate(0.99 g, 50%).

Tert-butyl(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate

To a solution of(2S,4S)-2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate(0.99 g, 1.9 mmol) in CH₂Cl₂ (18 mL) was added MnO₂ (4.52 g, 52.0 mmol).The resulting slurry was stirred at room temperature for 18 h. Thereaction was filtered through celite, washed with CH₂Cl₂, andconcentrated under reduced pressure. The crude residue was purified bysilica column chromatography (10% to 75% EtOAc(w/5% MeOH)/Hexanes) toafford tert-butyl(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate(0.71 g, 72%).

Methyl{(2S)-1-[(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To a solution of(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate(0.46 g, 0.9 mmol) in a mixture of CH₂Cl₂ (9.0 mL) and MeOH (1.5 mL) wasadded HCl (in dioxanes, 4M, 6.5 mL, 26.0 mmol). The resulting solutionwas stirred at room temperature for 2 h. The solution was concentratedto dryness under reduced pressure. To the crude intermediate in CH₂Cl₂(10.0 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(0.17 g, 0.9 mmol), HATU (0.41 g, 1.1 mmol), and DIPEA (0.5 mL, 2.9mmol). The resulting solution was stirred at room temperature for 48 hand diluted with CH₂Cl₂. The solution was washed with aqueous HCl (1N)and brine. The aqueous layers were backextracted with CH₂Cl₂ (2×). Theresulting organic layers were combined, dried (Na₂SO₄), and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc)to afford methyl{(2S)-1-[(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.46 g, 90%).

Methyl[(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate

To a solution of methyl{(2S)-1-[(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.46 g, 0.84 mmol) in dioxane (8.5 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.32 g, 1.3mmol), potassium acetate (0.25 g, 2.5 mmol),bis(dibenzylideneacetone)palladium (0.032 g, 0.035 mmol), and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos, 0.032 g,0.067 mmol). The resulting solution was degassed with argon for 5 minand heated, with stirring, to 90° C. for 6 h. The reaction was cooled toroom temperature, diluted with EtOAc, and filtered through celite. Thecrude residue was purified by silica column chromatography (20% to 100%EtOAc(w/5% MeOH)/Hexanes to 90% MeOH/EtOAc) to afford methyl[(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate(0.41 g, 73%).

Tert-butyl(2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

To a solution of methyl[(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate(0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) wasadded (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.39 g, 1.2mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). Thesolution was degasses with argon for 5 min and heated, with stirring, to85° C. for 6 h. The solution was cooled to room temperature and dilutedwith EtOAc. The organic layer was washed with water and brine. Theaqueous layers were backextracted with EtOAc (3×). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The crude residue was purified by silica column chromatography (20% to100% EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl(2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(0.16 g, 33%).

Methyl{(2S)-1-[(2S)-2-(5-{2-[(2S,4S)-4-ethoxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To a solution of tert-butyl(2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(0.048 g, 0.062 mmol) in a mixture of CH₂Cl₂ (1.0 mL) and MeOH (0.25 mL)was added HCl (in dioxanes, 4M, 0.47 mL, 1.9 mmol). The solution wasstirred at room temperature for 3 h, and then concentrated to drynessunder reduced pressure. To the crude intermediate suspended in CH₂Cl₂(1.5 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(0.012 g, 0.069 mmol), HATU (0.029 g, 0.076 mmol), and DIPEA (0.050 mL,0.28 mmol). The resulting solution was stirred at room temperature for1.5 h. The reaction was diluted with DMF and aqueous LiOH (2.5 M, 4drops) was added. The solution was concentrated to remove the CH₂Cl₂ andthe crude residue was purified by preparative reverse phase HPLC (10% to52% MeCN/water with 0.1% TFA). The desired fractions were combined andconcentrated under reduced pressure to remove volatile organics. Theaddition of aqueous sodium bicarbonate with stirring resulted inprecipitation of a white solid. The precipitate was filtered through amembrane filter and washed with water. Drying under reduced pressureafforded methyl{(2S)-1-[(2S)-2-(5-{2-[(2S,4S)-4-ethoxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.008 g, 17%). 1H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotomers) 8.37(s, 1H), 7.97 (s, 2H), 7.37-7.76 (m, 5H), 5.38-5.54 (m, 1H), 5.18 (s,2H), 5.14-5.16 (m, 1H), 4.21-4.31 (m, 4H), 3.87-4.09 (m, 1H), 3.79-3.85(m, 2H), 3.66 (s, 3H), 3.64 (s, 3H), 3.46-3.55 (m, 2H), 2.30-2.35 (m,3H), 2.04-2.06 (m, 3H), 1.11 (m, 2H), 0.95 (d, 3H), 0.88 (d, 3H). MS(ESI) m/z 836.02 [M+H]⁺.

Example OR

Methyl{(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-4-ethoxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

To a solution of tert-butyl(2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(0.11 g, 0.14 mmol) in a mixture of CH₂Cl₂ (2.0 mL) and MeOH (0.5 mL)was added HCl (in dioxanes, 4M, 1.0 mL, 4.0 mmol). The solution wasstirred at room temperature for 3 h, and then concentrated to drynessunder reduced pressure. To the crude intermediate suspended in CH₂Cl₂(1.5 mL) was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid(0.044 g, 0.21 mmol) and DIPEA (0.075 mL, 0.43 mmol). The resultingsolution was cooled to −40° C. and COMU (0.096 g, 0.22 mmol) was added.The reaction was allowed to slowly warm to 0° C. over 1 h. The reactionwas diluted with DMF. The solution was concentrated to remove the CH₂Cl₂and the crude residue was purified by preparative reverse phase HPLC(10% to 55% MeCN/water with 0.1% TFA). The desired fractions werecombined and concentrated under reduced pressure to remove volatileorganics. The addition of aqueous sodium bicarbonate with stirringresulted in precipitation of a white solid. The precipitate was filteredthrough a membrane filter and washed with water. Drying under reducedpressure afforded methyl{(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-4-ethoxy-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(0.022 g, 18%). 1H-NMR: 400 MHz, (MeOD) 6: (Mixture of rotomers) 8.28(d, 1H), 7.88 (d, 1H), 7.52-7.70 (m, 3H), 7.28-7.38 (m, 5H), 6.90-6.96(m, 2H), 5.44-5.47 (m, 1H), 5.31 (s, 1H), 5.12 (s, 2H), 4.16-4.48 (m,3H), 3.81-3.19 (m, 1H), 3.62-3.76 (m, 2H), 3.58 (s, 3H), 2.56 (s, 3H),2.42-2.57 (m, 1H), 2.31 (m, 1H), 1.81-2.41 (m, 5H), 1.04 (t, 3H), 0.87(d, 3H), 0.81 (d, 3H). MS (ESI) m/z 869.55 [M+H]⁺.

Example OS

Methyl(2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate

To a solution of (S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.00 g, 3.2 mmol)in a mixture of CH₂Cl₂ (30 mL) and MeOH (5 mL) was added HCl (indioxane, 4 M, 11.5 mL, 46.0 mmol). The solution was stirred at 40° C.for 1 h, cooled to room temperature, and concentrated to dryness underreduced pressure. To the crude intermediate suspended in CH₂Cl₂ (30 mL)was added (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.67g, 3.5 mmol), HATU (1.47 g, 3.8 mmol), and DIPEA (1.00 mL, 6.0 mmol),The resulting solution was stirred at room temperature for 24 h. DMF (2mL) and aqueous LiOH (2.5 M, 1 mL) were added and the reaction wasconcentrated to dryness under reduced pressure. The crude material wasdiluted with EtOAc and washed with H₂O and brine. The aqueous layerswere backextracted with EtOAc. The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The crude residuewas purified by silica column chromatography (20% to 100% EtOAc(w/5%MeOH)/CH₂Cl₂) to afford methyl(2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate(1.2g, 100%).

Example OT

Tert-butyl(2S,4S)-2-[9-(2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(1.0 g, 3.2 mmol) in a mixture of DMSO (2.0 mL) and dioxanes (2.0 mL)was added methyl(2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate(0.24 g, 0.62 mmol), tetrakis(triphenylphosphine)palladium (0.050 g,0.043 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 0.65 mL, 1.3mmol). The solution was degassed with argon for 5 min and heated, withstirring, to 85° C. for 6 h. The solution was cooled to room temperatureand diluted with EtOAc. The organic layer was washed with water andbrine. The aqueous layers were backextracted with EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄ and concentrated underreduced pressure. The crude residue was purified by silica columnchromatography (20% to 100% EtOAc(w/5% MeOH)/Hexanes to 60% MeOH/EtOAc)to afford tert-butyl (2S,4S)-2-[9-(2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.20 g, 63%).

Methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S)-1-{(2S,3R)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

To a solution of tert-butyl(2S,4S)-2-[9-(2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.20 g, 0.26 mmol) in a mixture of CH₂Cl₂ (3.0 mL) and MeOH (0.5 mL)was added HCl (in dioxanes, 4M, 2.0 mL, 8.0 mmol). The solution wasstirred at 40° C. for 1 h, and then cooled to room temperature andconcentrated to dryness under reduced pressure. To the crudeintermediate suspended in CH₂Cl₂ (3.0 mL) was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.081 g, 0.39 mmol)and DIPEA (0.150 mL, 0.86 mmol). The resulting solution was cooled to−40° C. and COMU (0.180 g, 0.42 mmol) was added. The reaction wasallowed to slowly warm to room temperature over 30 min and maintainedfor 1.5 h. The solution was diluted with CH₂Cl₂ and washed with aqueousbicarb. The aqueous layer was backextracted with CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The crude residue was purified by preparative reverse phaseHPLC (10% to 50% MeCN/water with 0.1% TFA). The desired fractions werecombined and concentrated under reduced pressure to remove volatileorganics. The addition of aqueous sodium bicarbonate with stirringresulted in precipitation of a white solid. The precipitate was filteredthrough a membrane filter and washed with water. Drying under reducedpressure afforded methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S)-1-{(2S,3R)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(0.10 g, 46%). 1H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotomers) 8.34 (s,1H), 7.92-7.97 (m, 2H), 7.33-7.69 (m, 10H), 5.53 (s, 1H), 5.36-5.39 (m,1H), 5.15-5.21 (m, 3H), 4.44 (d, 1H), 3.86-3.93 (m, 2H), 3.68-3.75 (m,2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.46-3.57 (m, 2H), 3.28 (s, 3H), 3.19(s, 3H), 2.47-2.60 (m, 311), 2.22-2.36 (m, 4H), 1.99-2.08 (m, 311), 1.15(d, 3H). MS (ESI) m/z 886.19 [M+H]⁺.

Example OU

Methyl(1-{4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methoxy-1-oxobutan-2-yl)carbamate

To a solution of tert-butyl4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(0.25 g, 0.41 mmol) in a mixture of CH₂Cl₂ (4.0 mL) and MeOH (1.0 mL)was added HCl (in dioxanes, 4M, 3.0 mL, 12.0 mmol). The resultingsolution was stirred at 40° C. for 45 min. The solution was cooled toroom temperature and concentrated to dryness under reduced pressure. Tothe crude intermediate in CH₂Cl₂ (4.0 mL) was added(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.08 g, 0.42mmol), HATU (0.17 g, 0.45 mmol), and DIPEA (0.4 mL, 2.3 mmol). Theresulting solution was stirred at room temperature for 48 h and dilutedwith CH₂Cl₂. The solution was washed with brine. The aqueous layer wasbackextracted with CH₂Cl₂ (2×). The resulting organic layers werecombined, dried (Na₂SO₄), and concentrated under reduced pressure. Thecrude residue was purified by silica column chromatography (30% to 100%EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl(1-{4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methoxy-1-oxobutan-2-yl)carbamate(0.24 g, 92%).

Tert-butyl(2S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

To a solution of methyl(1-{4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methoxy-1-oxobutan-2-yl)carbamate(0.15 g, 0.22 mmol) in a mixture of DMSO (2.0 mL) and dioxane (2.0 mL)was added (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.15 g, 0.40mmol), tetrakis(triphenylphosphine)palladium (0.028 g, 0.024 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.018 g, 0.025mmol), and aqueous potassium carbonate (2M, 0.35 mL, 0.70 mmol). Thesolution was degassed with argon for 5 min and heated, with stirring, to90° C. for 6 h. The solution was cooled to room temperature and dilutedwith EtOAc. The organic layer was washed with water and brine. Theaqueous layers were backextracted with EtOAc (3×). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure.The crude residue was purified by preparative reverse phase HPLC (10% to55% MeCN/water with 0.1% TFA). The desired fractions were combined andconcentrated under reduced pressure to remove volatile organics. Theremaining solution was basified with aqueous bicarbonate and extractedwith CH₂Cl₂ (3×). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure to provide tert-butyl(2S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.013 g, 7%).

Methyl{(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methoxybutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazo-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

To a solution of tert-butyl(2S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(0.013 g, 0.016 mmol) in a mixture of CH₂Cl₂ (0.5 mL) and MeOH (0.02 mL)was added HCl (in dioxanes, 4M, 0.20 mL, 0.80 mmol). The solution wasstirred at room temperature for 1 h, and then concentrated to drynessunder reduced pressure. To the crude intermediate suspended in CH₂Cl₂(0.5 mL) was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid(0.006 g, 0.029 mmol) and DIPEA (0.05 mL, 0.28 mmol). The resultingsolution was cooled to 0° C. and COMU (0.012 g, 0.028 mmol) was added.The reaction was stirred at 0° C. for 30 min. The solution was dilutedwith DMF and aqueous LiOH (2.5 M, 2 drops) and concentrated underreduced pressure to remove the CH₂Cl₂. The crude residue was purified bypreparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA).The desired fractions were combined and concentrated under reducedpressure to remove volatile organics. The addition of aqueous sodiumbicarbonate with stirring resulted in precipitation of a white solid.The precipitate was filtered through a membrane filter and washed withwater. Drying under reduced pressure afforded methyl{(1R)-2-[(2S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methoxybutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(0.008 g, 61%). ¹H-NMR: 400 MHz, (MeOD) 6: (Mixture of rotomers) 8.37(m, 1H), 7.96-7.98 (m, 2H), 7.60-7.79 (m, 3H), 7.35-7.52 (m, 6H),6.98-7.03 (m, 1H), 5.52 (s, 1H), 5.26-5.39 (m, 2H), 5.20 (s, 2H), 4.44(m, 1H), 4.27 (m, 1H), 3.64 (s, 6H), 3.50-3.57 (m, 3H), 3.37 (s, 3H),3.29-3.44 (m, 3H), 3.20 (s, 3H), 2.68-2.72 (m, 2H), 2.57-2.62 (m, 2H),1.89-2.15 (m, 6H), 1.18 (d, 3H). MS (ESI) m/z 885.73 [M+H]⁺.

Example OV

Methyl[(2S)-1-{(2S,4S)-3-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-2-azabicyclo[3.1.0]hex-2-yl}-3-methyl-1-oxobutan-2-yl]carbamate

Methyl[(2S)-1-{(2S,4S)-3-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-2-azabicyclo[3.1.0]hex-2-yl}-3-methyl-1-oxobutan-2-yl]carbamatewas prepared following the procedure for methyl[(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamateby substitution of (1 S,3 S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acidfor (2S,4S)-1-(tert-butoxycarbonyl)-4-ethoxypyrrolidine-2-carboxylicacid.

Tert-butyl (2S,4S)-2-[5-(2-{(1S,3S,5S)-2-[N-(methoxycarbonyl)-L-valyl]-2-azabicyclo[3.1.0]hex-3-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of methyl[(2S)-1-{(2S,4S)-3-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-2-azabicyclo[3.1.0]hex-2-yl}-3-methyl-1-oxobutan-2-yl]carbamate(0.19 g, 0.30 mmol) in a mixture of DMSO (2.0 mL) and dioxane (2.0 mL)was added (2S,4S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.20 g, 0.55 mmol), tetrakis(triphenylphosphine)palladium (0.035 g,0.030 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(0.025 g, 0.034 mmol), and aqueous potassium carbonate (2M, 0.5 mL, 1.0mmol). The solution was degassed with argon for 5 min and heated, withstirring, to 90° C. for 6 h. The solution was cooled to roomtemperature, diluted with EtOAc, and filtered through celite. Thefiltrate was concentrated under reduced pressure and purified by silicacolumn chromatography (2% to 25% CH₂Cl₂/MeOH) and preparative reversephase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractionswere combined and concentrated under reduced pressure to remove volatileorganics. The aqueous layer was basified with aqueous sodium bicarbonateand extracted with CH₂Cl₂ (3×). The organic layers were combine, driedover Na₂SO₄, and concentrated under reduced pressure to affordtert-butyl(2S,4S)-2-[5-(2-{(1S,3S,5S)-2-[N-(methoxycarbonyl)-L-valyl]-2-azabicyclo[3.1.0]hex-3-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.025 g, 11%).

Methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(1S,3S,5S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

To a solution of tert-butyl (2S,4S)-2-[5-(2-{(1 S,3 S,5S)-2-[N-(methoxycarbonyl)-L-valyl]-2-azabicyclo[3.1.0]hex-3-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.025 g, 0.032 mmol) in a mixture of CH₂Cl₂ (1.0 mL) and MeOH (0.25 mL)was added HCl (in dioxanes, 4M, 0.50 mL, 2.0 mmol). The solution wasstirred at room temperature for 12 h, and then concentrated to drynessunder reduced pressure. To the crude intermediate suspended in CH₂Cl₂(0.5 mL) was added (R)-2-(methoxycarbonylamino)-2-phenylacetic acid(0.012 g, 0.057 mmol) and DIPEA (0.05 mL, 0.28 mmol). The resultingsolution was cooled to 0° C. and COMU (0.023 g, 0.054 mmol) was added.The reaction was stirred at 0° C. for 30 min. The solution was dilutedwith DMF and aqueous LiOH (2.5 M, 2 drops) and concentrated underreduced pressure to remove the CH₂Cl₂. The crude residue was purified bypreparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA).The desired fractions were combined and concentrated under reducedpressure to remove volatile organics. The addition of aqueous sodiumbicarbonate with stirring resulted in precipitation of a white solid.The precipitate was filtered through a membrane filter and washed withwater. Drying under reduced pressure afforded methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(1S,3S,5S)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(0.015 g, 55%). ¹H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotomers) 8.35(m, 1H), 7.94-7.96 (m, 2H), 7.54-7.78 (m, 6H), 6.93-7.00 (m, 1H), 5.72(m, 1H), 5.46 (s, 1H), 5.19 (s, 2H), 5.14-5.16 (m, 1H), 3.95 (m, 1H),3.67 (s, 3H), 3.63 (s, 3H), 3.42-3.49 (m, 2H), 3.24 (s, 3H), 2.67-2.78(m, 2H), 2.41-2.62 (m, 3H), 2.01-2.13 (m, 2H), 1.86-1.99 (m, 3H),0.99-1.03 (m, 2H), 0.90 (d, 3H). MS (ESI) m/z 882.23 [M+H]⁺.

Example OW

Tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

To a solution of methyl(1-{4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl)carbamate(0.47 g, 0.78 mmol) in a mixture of DMSO (4.0 mL) and dioxane (4.0 mL)was added methyl(2S,3S)-1-((2S,5S)-2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate(0.26 g, 0.72 mmol), tetrakis(triphenylphosphine)palladium (0.090 g,0.078 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(0.061 g, 0.083 mmol), and aqueous potassium carbonate (2M, 1.2 mL, 2.4mmol). The solution was degassed with argon for 5 min and heated, withstirring, to 90° C. for 6 h. The solution was cooled to roomtemperature, diluted with EtOAc, and filtered through celite. Thefiltrate was concentrated under reduced pressure and diluted with EtOAc.The organic solution was washed water and brine and the aqueous layerswere backextracted with EtOAc. The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure. The crude residuewas purified by silica column chromatography (10% to 100% EtOAc (5%MeOH)/CH₂Cl₂) to afford tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.25 g, 40%).

Methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S,5S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

To a solution of tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.175 g, 0.21 mmol) in a mixture of CH₂Cl₂ (2.0 mL) and MeOH (0.5 mL)was added HCl (in dioxanes, 4M, 1.6 mL, 6.4 mmol). The solution wasstirred at 40° C. for 1 h, cooled to room temperature, and thenconcentrated to dryness under reduced pressure. To the crudeintermediate suspended in CH₂Cl₂ (3.0 mL) was added(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.070 g, 0.34 mmol)and DIPEA (0.15 mL, 0.86 mmol). The resulting solution was cooled to−40° C. and COMU (0.15 g, 0.35 mmol) was added. The reaction was warmedto room temperature over 30 min and diluted with CH₂Cl₂. The solutionwas washed with saturated aqueous sodium bicarbonate. The aqueous layerwas backextracted with CH₂Cl₂, and the combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. The cruderesidue was purified by preparative reverse phase HPLC (10% to 58%MeCN/water with 0.1% TFA). The desired fractions were combined andconcentrated under reduced pressure to remove volatile organics. Theaddition of aqueous sodium bicarbonate with stirring resulted inprecipitation of a white solid. The precipitate was filtered through amembrane filter and washed with water. Drying under reduced pressureafforded methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S,5S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(0.079 g, 41%). ¹H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotomers) 8.36(m, 1H), 7.93-7.98 (m, 2H), 7.66-7.84 (m, 3H), 7.35-7.48 (m, 7H), 5.53(s, 1H), 5.36-5.39 (m, 1H), 5.17 (d, 2H), 5.08 (m, 1H), 4.14-4.35 (m,1H), 3.74 (m, 4H), 3.64 (s, 3H), 3.62 (s, 3H), 3.46 (m, 1H), 3.19 (s,3H), 2.76 (m, 1H), 2.46-2.60 (m, 3H), 2.24-2.35 (m, 1H), 2.08-2.18 (m,2H), 1.91 (m, 1H), 1.61-1.87 (m, 2H), 1.48 (d, 3H), 1.13-1.21 (m, 3H),0.80-0.97 (m, 3H). MS (ESI) m/z 898.24 [M+H]⁺.

Example OX

Methyl{(2S)-1-[(2S,4S)-2-(9-{2-[(2S,5S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To a solution of tert-butyl(2S,4S)-2-[9-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-isoleucyl]-5-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.075 g, 0.09 mmol) in a mixture of CH₂Cl₂ (1.0 mL) and MeOH (0.25 mL)was added HCl (in dioxanes, 4M, 0.7 mL, 2.8 mmol). The solution wasstirred at 40° C. for 1 h, cooled to room temperature, and thenconcentrated to dryness under reduced pressure. To the crudeintermediate suspended in CH₂Cl₂ (3.0 mL) was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.020 g, 0.14 mmol),HATU (0.043 g, 0.11 mmol) and DIPEA (0.10 mL, 0.57 mmol). The reactionwas stirred at room temperature for 2 h. The reaction was diluted withDMF and aqueous LiOH (2.5 M, 3 drops) and the CH₂Cl₂ was removed underreduced pressure. The crude residue was purified by preparative reversephase HPLC (10% to 58% MeCN/water with 0.1% TFA). The desired fractionswere combined and concentrated under reduced pressure to remove volatileorganics. The addition of aqueous sodium bicarbonate with stirringresulted in precipitation of a white solid. The precipitate was filteredthrough a membrane filter and washed with water. Drying under reducedpressure afforded methyl{(2S)-1-[(2S,4S)-2-(9-{2-[(2S,5S)-1-{(2S,3S)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.031 g, 38%). ¹H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotomers) 8.34(m, 1H), 7.91-9.97 (m, 2H), 7.50-7.81 (m, 3H), 7.35-7.38 (m, 2H),5.17-5.26 (m, 3H), 5.08 (m, 1H), 4.14-4.33 (m, 4H), 3.64 (s, 3H), 3.63(s, 3H), 3.51-3.59 (m, 3H), 3.37 (s, 3H), 2.71 (m, 1H), 2.55-2.59 (m,1H), 2.23-2.33 (m, 1H), 1.92-2.10 (m, 2H), 1.77-1.89 (m, 1H), 1.60 (m,1H), 1.48 (d, 1H), 1.11-1.22 (m, 2H), 0.81-0.98 (m, 12H). MS (ESI) m/z864.27 [M+H]⁺.

Example OY

(S)-2-(methoxycarbonylamino)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methylbutan-1-one

(3S,3′S,5S,5′S)-tert-butyl5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(3-methylpyrrolidine-1-carboxylate)was obtained as in example LL but using(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid inplace of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. (3S,3′S,5 S,5′S)-tert-butyl5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(3-methylpyrrolidine-1-carboxylate)(500 mg, 0.706 mmol) was treated with 5.7 mL 1.25N HCl in ethanol andheated at 50° C. for 4 hours. The reaction mixture was concentratedunder reduced pressure to give2,7-bis(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene.A mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (124 mg,0.706 mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (148 mg,0.706 mmol), COMU (665 mg, 1.55 mmol) in DMF was allowed to preactivatefor 15 minutes before it was added to the crude amine in 3.5 mL DMF and0.74 mL DIPEA. Once starting material was consumed, by LCMS monitoring,the reaction mixture was neutralized with formic acid, diluted withmethanol and purified by reverse phase HPLC in 6 injections to providethree products, two homodimers and the heterodimer(S)-2-(methoxycarbonylamino)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methylbutan-1-one(220.3 mg) as a salt of trifluoroacetic acid.

MS (ESI) m/z 857.1 [M+H]⁺;

¹H NMR (CD₃CN) 7.46-7.31 (m, 7H), 6.901-6.746 (m, 4H), 6.045 (m, 1H),5.222 (d, 1H, J=7.6 Hz), 5.169 (m, 1H), 5.095 (d, 4H, J=7.2 Hz), 4.370(m, 1H), 4.158 (m, 1H), 3.775 (m, 1H), 3.630 (s, 6H), 3.533 (m, 2H),2.487 (m, 6H), 2.229 (m, 2H), 1.777 (m, 1H), 1.162 (d, 3H, J=6.0 Hz),1.073 (d, 3H, J=6.4 Hz), 1.024 (d, 3H, J=6.8 Hz), 0.929 (d, 3H, J=6.4Hz).

Example OZ

(S)-2-(methoxycarbonylamino)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(t-butoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methylbutan-1-one

2,7-bis(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromenewas obtained as in Example OY. A mixture of(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (124 mg, 0.7O6 mmol),(R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (177 mg, 0.7O6mmol), COMU (665 mg, 1.55 mmol) in 3.7 mL DMF was allowed to preactivatefor 20 minutes before it was added to 449 mg of the crude amine in 3.7mL DMF with 0.74 mL DIPEA. Once starting material was consumed, by LCMSmonitoring, the reaction mixture was neutralized with formic acid,diluted with methanol and purified by reverse phase HPLC three products,two homodimers and the heterodimer(S)-2-(methoxycarbonylamino)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(t-butoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methylbutan-1-oneas the trifluoroacetate salts. The eluted fractions were concentratedunder reduced pressure, basified with saturated sodium bicarbonatesolution and extracted into dichloromethane. Concentration under reducedpressure gave product (86 mg).

methyl(S)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-2-(methoxycarbonylamino)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(t-butoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methylbutan-1-one,86 mg, was treated with 0.76 mL 1.25N HCl in Ethanol at room temperatureovernight, then at 50° C. for 1 hour. The mixture was concentrated underreduced pressure and further dried under high vacuum to give product (90mg).

Methyl(S)-3-methyl-1-((2S,4S)-4-methyl-2-(5-(7-(2-((2S,4S)-4-methyl-1-((R)-2-phenyl-2-(2,2,3,3-tetramethylcyclopropanecarboxamido)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate

Methyl(S)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-amino-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(45 mg, 0.049 mmol) in 0.5 mL 10% DIPEA in DMF was added to a mixture of2,2,3,3-tetramethylcyclopropanecarboxylic acid (8.4 mg, 0.059 mmol) andHATU (22 mg, 0.059 mmol) in 0.2 mL 10% DIPEA in DMF. After 20 minutesstirring at room temperature, the reaction mixture was diluted with 0.2mL water, 5 drops formic acid, and methanol to a total volume of 2.4 mLand purified by reverse phase HPLC to give 22.6 mg product as atrifluoroacetate salt.

MS (ESI) m/z 923.9 [M+H]⁺.

Example PA

(2S,4S)-Benzyl2-(5-(7-(2-((2S,4S)-1-tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

A mixture of1,1′-(5,10O-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-bromoethanone)(1.27g, 2.8 mmol),(2S,4S)-1-(benzyloxycarbonyl)-4-methylpyrrolidin-2-carboxylic acid (810mg, 3.08 mmol), and(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (800 mg, 3.08 mmol) in 28 mL THF with 0.98 mL triethylamine washeated at 80° C. overnight. This gave a crude mixture of three diesterproducts. The reaction mixture was partitioned between ethyl acetate andwater, and further extracted the aqueous layer with ethyl acetate. Thecombined organic phase was dried over sodium sulphate, filtered,concentrated and then treated directly with ammonium acetate (2.17g, 28mmol), toluene (28 mL) and 2-methoxypropanol (2.8 mL) and heated atreflux for 26 hours. The crude product mixture of three bis-imidazoleproducts was concentrated and the three products were separated byreverse phase HPLC. Product (2S,4S)-benzyl2-(5-(7-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate,490 mg, was isolated by concentration of the appropriate fraction,basification with saturated sodium bicarbonate, extraction intodichloromethane, and concentration under reduced pressure.

(2S,4S)-tert-butyl4-(methoxymethyl)-2-(5-(7-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of (2S,4S)-benzyl2-(5-(7-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(475 mg, 0.591 mmol) 60 mL ethanol, and 92 mg 10% Pd/C was stirred underan atmosphere of hydrogen (balloon) overnight. Filtration throughcelite, concentration and purification by reverse phase HPLC gave(2S,4S)-tert-butyl4-(methoxymethyl)-2-(5-(7-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylateas a trifluoroacetate salt. Addition of saturated sodium bicarbonatesolution, extraction into ethyl acetate and concentration of the extractgave 102 mg as the free base.

(2S,4S)-tert-butyl2-(5-(7-(2-((2S,4S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

A mixture of (2S,4S)-tert-butyl4-(methoxymethyl)-2-(5-(7-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(102 mg, 0.159 mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid(33 mg, 0.159 mmol), COMU (75 mg, 0.175 mmol) in 1.59 mL 10% DIPEA inDMF was stirred at room temperature for 1 hr. Saturated sodiumbicarbonate was added and the crude product was extracted into ethylacetate. Concentration and purification by silica gel chromatographygave product (245 mg).

methyl(R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

A mixture of (2S,4S)-tert-butyl2-(5-(7-(2-((2S,4S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(245 mg) and 5 mL 1.25N HCl in ethanol was stirred at room temperatureovernight, then at 60° C. for 1 hour, then concentrated to an orangesolid as an HCl salt (180 mg) that was used without furtherpurification.

(S)-2-(methoxycarbonylamino)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methylbutan-1-one

A mixture of methyl(R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(90 mg, >0.123 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(24 mg, 0.135 mmol), HATU (51 mg, 0.135 mmol) in 1.5 mL 10% DIPEA in DMFwas stirred for 1 hour. An additional 0.135 mmol of(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid and HATU were addedand stirring continued for 4 hours. The crude product was purified byreverse phase HPLC to product (28 mg) as a trifluoroacetate salt.

MS (ESI) m/z 887.1 [M+H]⁺;

¹H NMR (CD₃CN) 7.460-7.314 (m, 6H), 6.907-6.807 (m, 3H), 6.746 (m, 1H),6.042 (m, 1H), 5.518 (d, 1H, J=7.2 Hz), 5.166 (m, 1H), 5.095 (d, 4H,J=7.2 Hz), 4.348 (m, 1H), 4.181 (m, 1H), 3.718 (m, 1H), 3.634 (s, 6H),3.495 (m, 2H), 3.334 (m, 3H), 2.641 (m, 2H), 2.488 (m, 4H), 2.205 (m,2H), 2.070 (m, 4H), 1.073 (d, 3H, J=6.4 Hz), 1.020 (d, 3H, J=6.8 Hz),0.934 (d, 3H, J=6.4 Hz).

Example PB

Methyl(R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((2S,3R)-2-(methoxycarbonylamino)-3-methoxybutanoyl)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate

A mixture of methyl(R)-2-((2S,4S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate(90 mg, >0.123 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoicacid (26 mg, 0.135 mmol), HATU (51 mg, 0.135 mmol) in 1.5 mL 10% DIPEAin DMF was stirred for 1 hour. An additional 0.135 mmol of(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid and HATU wereadded and stirring continued for 3 hours. The crude product was purifiedby reverse phase HPLC to product (22 mg) as a trifluoroacetate salt.

MS (ESI) m/z 903.2 [M+H]⁺;

¹H NMR (CD₃OD) 7.850 (m, 2H), 7.449 (m, 5H), 7.359 (s, 1H), 7.263 (s,2H), 7.220 (s, 1H), 5.420 (s, 1H), 5.360 (d, 4H, J=2.2 Hz), 5.261 (m,1H), 5.197 (m, 1H), 4.478 (m, 1H), 4.266 (m, 1H), 4.118 (m, 1H), 3.684(m, 1H), 3.684 (s, 6H), 3.623 (s, 3H), 3.550 (m, 2H), 3.408 (s, 3H),2.771 (m, 1H), 2.628 (m, 2H), 2.278 (m, 1H), 2.055 (m, 1H), 1.780 (m,1H), 1.345 (t, 2H, J=7.0 Hz), 1.128 (d, 6H, J=6.0 Hz).

Example PC

(2S,5R)-dimethyl-1-benzylpyrrolidine-2,5-dicarboxylate

To an 80° C. solution of (2R,5S)-dimethyl 2,5-dibromohexanedioate(25.0g, 69.0 mmol) in 100 mL toluene was added benzylamnine (25.2 mL,230 mmol) drop wise over 30 minutes. After 16 hours at 80° C., thereaction was cooled to room temperature and filtered. The filter cakewas washed with three 60 mL portions of toluene and the combinedfiltrate was washed with water and saturated ammonium chloride, thenconcentrated under reduced pressure to give 21.63g product whose NMR isconsistent with the title compound.

(2S,5R)-1-tert-butyl 2,5-dimethyl pyrrolidine-1,2,5-tricarboxylate

A 0.05M solution of (2S,5R)-dimethyl1-benzylpyrrolidine-2,5-dicarboxylate (1.53g, 5.0 mmol) in methanolcontaining di-tert-butyl dicarbonate (1.18g, 5.5 mmol) was hydrogenatedby 1 mL/min flow through a 55 mm 20% Pd(OH)₂ catalyst cartridge atatmospheric pressure with full H₂ saturation. The effluent wasconcentrated under reduced pressure and further dried under high vacuumovernight to give 2.21g product as a colorless oil.

(2S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-2-carboxylicacid

(2S,5R)-1-tert-butyl 2,5-dimethyl pyrrolidine-1,2,5-tricarboxylate(2.21g, 7.01 mmol) was suspended in 100 mL pH 7.5 phosphate buffer andtreated with Pig Liver Esterase (500 mg) at 25° C. for 10 days, withoccasional pH adjustment to maintain pH 7.5. Acidified to pH 4 with 2NHCl and extracted into dichloromethane. The extract was dried oversodium sulphate, filtered, and concentrated under reduced pressure togive 1.17g crude product.

(2S,5R)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidine-2-carboxylicacid

To an ice cold solution of(2S,5R)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-2-carboxylicacid (1.17g, 4.07 mmol) in 70 mL diethyl ether and 0.330 mL methanol wasadded lithium borohydride (2M in THF, 4.0 mL, 8.14 mmol). After 10minutes, the ice bath was removed and the reaction was heated at refluxovernight. As the reaction had not proceeded, a solvent swap to THF wasperformed, and the resulting mixture was heated at 70° C. overnight. Thereaction mixture was cooled to 0° C. and quenched with 1N HCl and thenextracted into ethyl acetate, dried over sodium sulphate, filtered andconcentrated under reduced pressure to give the crude product as a whitesemi-solid (886 mg)

(2S,5R)-1-(tert-butoxycarbonyl)-5-(methoxymethyl)pyrrolidine-2-carboxylicacid

A solution of(2S,5R)-1-(tert-butoxycarbonyl)-5-(hydroxymethyl)pyrrolidine-2-carboxylicacid (820 mg, 3.34 mmol) in 11 mL THF was cooled in a −10° C. bath andtreated with n-butyl lithium (1.6M in hexanes, 6.5 mL, 10.36 mmol) andkept cold for 1 hour, then dimethyl sulphate (0.380 mL, 4.01 mmol) wasadded. The temperature was held at −5° C. to 5° C. and then the reactionmixture was held in the −20° C. freezer overnight. The reaction wasquenched cold, with water. Next, the mixture was concentrated underreduced pressure to remove THF. The aqueous mixture was acidified with2N HCl and extracted with ethyl acetate. The organic layer was driedover sodium sulphate, filtered, and concentrated under reduced pressureto give 788 mg crude product, which was then purified by silica gelchromatography to give 199 mg clean product, 140 mg recovered startingmaterial, and 317 mg of a mixture of starting material and product.

(2S,2′S,5R,5′R)-1-tert-butyl‘2,2-2,2’-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-oxoethane-2,1-diyl)bis(5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate)

A mixture of1,1′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-bromoethanone)(139 mg, 0.31 mmol)), and(2S,5R)-1-(tert-butoxycarbonyl)-5-(methoxymethyl)pyrrolidine-2-carboxylicacid (199 mg, 0.77 mmol) in 3 mL DMF with 0.107 mL triethylamine washeated at 80° C. for 4 hours. Water (10 mL) was added and theprecipitate that formed was collected by vacuum filtration, washed withwater, and air dried for 1 hour before drying under high vacuumovernight to give crude product (229 mg) as a dark yellow solid.

(2R,2′R,5S,5′S)-tert-butyl5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-(methoxymethyl)pyrrolidine-1-carboxylate)

A mixture of (2S,2′S,5R,5′R)-1-tert-butyl‘2,2-2,2’-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-oxoethane-2,1-diyl)bis(5-(methoxymethyl)pyrrolidine-1,2-dicarboxylate)(204 mg, 0.252 mmol), ammonium acetate (195 mg, 2.52 mmol), toluene (2.5mL) and 2-methoxypropanol (0.25 mL) was heated at 110° C. overnight. Themixture was concentrated under reduced pressure and purified by silicagel chromatography. (254 mg)

2,7-bis(2-((2S,5R)-5-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromene

A solution of (2R,2′R,5S,5′S)-tert-butyl5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(H-imidazole-5,2-diyl))bis(2-(methoxymethyl)pyrrolidine-1-carboxylate)(254 mg, 0.33 mmol) and 1.25N HCl in ethanol (6 mL) was heated at 50° C.for 3 hours, then concentrated under reduced pressure and further driedunder high vacuum and used in the next step.

dimethyl(2S,2′S)-1,1′-((2R,2′R,5S,5′S)-5,5′-(5,510-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-(methoxymethyl)pyrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

A solution of2,7-bis(2-((2S,5R)-5-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromenefrom the previous step, (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (127 mg, 0.726 mmol), HATU (276 mg, 0.0726 mmol) and DIPEA (0.576mL, 3.3 mmol) in DMF (1.8 mL) was stirred at room temperature for 1hour. The crude product was purified by reverse phase HPLC to give theproduct as a trifluoroacetate salt (75.7 mg)

MS (ESI) m/z 883.8 [M+H]⁺;

¹H NMR (CD₃CN) 7.62 (m, 1H), 7.526 (m, 1H), 7.281 (m, 1H), 7.208 (m,1H), 7.128 (m, 1H), 7.052 (m, 1H), 6.073 (m, 1H), 5.724 (m, 1H),5.389-5.201 (m, 4H), 4.240 (m, 1H), 4.070 (m, 1H), 4.070 (m, 1H), 3.962(s, 1H), 3.615 (m, 2H), 3.507 (m, 8H), 3.332 (m, 6H), 2.375 (m, 2H),2.303 (m, 4H), 2.128 (m, 2H), 2.108 (m, 4H), 0.966 (m, 12H).

Example PE

Methyl(2S,3R)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamateand Dimethyl(2S,2′S,3R,3′R)-1,1′-((3S,3′S,5S,5′S)-5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate

(3S,3′S,5S,5′S)-tert-butyl5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(3-methylpyrrolidine-1-carboxylate)(321 mg, 0.63 mmol) was deprotected with 4 mL 1.25N HCl in ethanol at50° C. for 2 hours, then concentrated. A mixture of(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (131 mg, 0.67mmol) and HATU (251 mg, 0.67 mmol), in 3 mL 10% DIPEA in DMF was mixedand then was added to the crude amine. An additional portion of(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (48 mg) and HATU(80 mg) were added. After 2 hours at room temperature,(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (100 mg) and COMU (400mg) was added and the reaction was allowed to stir at room temperaturefor 3 hours. The intermediate and title compounds were purified from theproduct mixture by reverse phase HPLC as salts of trifluoroacetic acid.

Dimethyl(2S,2′S,3R,3′R)-1,1′-((3S,3′S,5S,5′S)-5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(3-methylpyrrolidine-5,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate(59.5 mg)

MS (ESI) m/z 855.2 [M+H]⁺;

¹H NMR (CD₃CN) 7.296 (m, 2H), 7.214 (m, 4H), 5.861 (m, 2H), 5.240 (s,4H), 5.085 (m, 2H), 4.710 (m, 2H), 4.061 (m, 2H), 3.637 (s, 6H), 3.630(m, 2H), 3.292 (m, 2H), 3.212 (s, 6H), 2.469 (m, 2H), 2.320 (m, 2H),1.147 (d, 6H, J=6.4 Hz), 1.087 (m, 6H).

Methyl(2S,3R)-3-methoxy-1-((2S,4S)-4-methyl-2-(5-(7-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-1-oxobutan-2-ylcarbamate(intermediate, 46 mg, 0.0675 mmol) was then treated with more(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (14 mg, 0.0675 mmol)and COMU (29 mg, 0.0675 mmol) in 1 mL 10% DIPEA in DMF at roomtemperature for 1 hour. The mixture was partitioned between saturatedsodium bicarbonate and ethyl acetate. The organic layer was dried oversodium sulphate, filtered, and concentrated, then purified by reversephase HPLC to give the product as a trifluoroacetate salt. (18.6 mg)

MS (ESI) m/z 873.7 [M+H]⁺;

¹H NMR (CDCl₃) 7.389 (m, 5H), 7.177 (m, 6H), 5.720 (m, 1H), 5.401 (m,1H), 5.219 (m, 6H), 4.559 (m, 1H), 3.969 (m, 1H), 3.691 (s, 3H), 3.645(s, 3H), 3.589 (m, 2H), 3.54 (m, 1H), 3.173 (s, 3H), 2.507 (m, 2H),2.427 (m, 2H), 2.348 (m, 1H), 1.826 (m, 2H), 1.167 (m, 6H), 1.036 (m,3H).

Example PF

tert-butyl(2S,4S)-4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate

The title compound was obtained as in example LQ but using(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid in place of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid.

2-[4-(methoxymethyl)pyrrolidin-2-yl]-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazole

Tert-butyl(2S,4S)-4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylate(310 mg, 0.507 mmol) was treated with 2 mL 1.25N HCl in ethanol andstirred at room temperature for 2 h then at 50° C. for 2 h. The reactionmixture was concentrated under reduced pressure to give a dark yellowsolid that was used directly in the next step.

methyl[(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate

A mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (107 mg,0.608 mmol), HATU (231 mg, 0.608 mmol) and 6 mL 10% DIPEA in DMF waspre-activated for 5 minutes, then it was added to the amine salt fromthe step above and allowed to stir overnight. The reaction mixture waspartitioned between ethyl acetate and saturated sodium bicarbonate. Theorganic phase was concentrated and purified by silica gelchromatography. (103 mg)

tert-butyl2-[5-(2-{1-[N-(methoxycarbonyl)valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate

the title compound was obtained as in example LQ but using methyl[(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate(103 mg, 0.154 mmol) in place of tert-butyl2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylateand methyl(S)-1-((S)-2-(5-iodo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(58 mg, 0.154 mmol) in place of methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.(50.0 mg)

methyl{1-[4-(methoxymethyl)-2-{9-[2-(4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

tert-butyl2-[5-(2-{1-[N-(methoxycarbonyl)valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(50 mg, 0.063 mmol) was treated with 2 mL 1.25N HCl in ethanol andheated at 60° C. for 2 h, then it was concentrated under reducedpressure and pumped dry under high vacuum and used directly in the nextstep.

methyl{1-[2-{9-[2-(1-{[(methoxycarbonyl)amino](phenyl)acetyl}-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl}-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A mixture of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (13 mg,0.063 mmol), COMU (30 mg, 0.069 mmol) in 0.500 mL DMF and DIPEA (0.033mL, 0.189 mmol) was allowed to preactivate for 15 minutes before it wasadded to the solid crude amine salt from the previous step and stirredovernight. The product was purified by reverse phase HPLC. The productwas converted to the free base by dissolution in 2 mL 1:1acetonitrile:methanol and passage through a prepacked cartridge ofpolymer supported carbonate. Concentration and drying gave an off whitepowder. (23.3 mg).

MS (ESI) m/z 883.8 [M+H]⁺

¹H NMR (CD₃CN) 8.176 (s, 1H), 7.778 (m, 1H), 7.596-7.521 (m, 4H),7.455-7.347 (m, 6H), 7.218 (s, 1H), 5.482 (s, 1H), 5.310 (m, 1H), 5.192(m, 1H), 4.999 (q, 2H, J=14 Hz), 4.372 (d, 1H, J=6.4 Hz), 4.279 (m, 1H),3.800-3.697 (m, 2H), 3.632 (s, 3H) 3.597-3.445 (m, 7H), 3.355 (s, 3H),2.876 (m, 2H), 2.761 (m, 1H), 2.583 (m, 2H), 2.220 (m, 2H), 1.764 (m,1H), 1.070 (d, 3H, J=6.4 Hz), 1.020 (d, 3H, J=6.4 Hz), 0.898 (d, 3H,J=6.4 Hz).

Example PG

tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate

The title compound was obtained as in example LQ but using methyl[(2S)-3-methyl-1-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate(307 mg, 0.481 mmol) in place of tert-butyl2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidine-1-carboxylateand methyl(S)-1-((S)-2-(5-iodo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(181 mg, 0.481 mmol) in place of methyl(S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate.(200.8 mg)

methyl{(2S)-3-methyl-1-[(2S,4S)-4-methyl-2-(9-{2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(200 mg, 0.262 mmol) was treated with 2 mL 1.25N HCl in ethanol andheated at 60° C. for 2 h, then it was concentrated under reducedpressure and pumped dry under high vacuum and used directly in the nextstep.

methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A mixture of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (13 mg,0.063 mmol), COMU (30 mg, 0.069 mmol) in 1.5 mL DMF was allowed topreactivate for 5 minutes before it was added to a solution of the aminefrom the previous salt in 1.5 mL DMF and DIPEA (0.137 mL, 0.786 mmol)and stirred overnight. The product was purified by reverse phase HPLC.The product was converted to the free base by dissolution in 2 mL 1:1acetonitrile:methanol and passage through a prepacked cartridge ofpolymer supported carbonate. Concentration and drying gave an off whitepowder. (25.8 mg).

MS (ESI) m/z 853.8 [M+H]⁺.

¹H NMR (CD₃CN) 8.164 (s, 1H), 7.781 (m, 1H), 7.609 (m, 2H), 7.535 (m,2H), 7.433-7.305 (m, 6H), 7.229 (s, 1H), 5.482 (s, 1H), 5.290 (m, 1H),5.191 (m, 1H), 4.997 (m, 2H), 4.372 (d, 1H, J=6.4 Hz), 4.267 (m, 1H),3.735-3.445 (m, 10H), 2.573 (m, 4H), 2.197 (m, 2H), 2.017 (m, 1H), 1.760(m, 1H), 1.204 (d, 3H, J=6.4 Hz), 1.068 (d, 3H, J=6.4 Hz), 1.010 (d, 3H,J=6.8 Hz), 0.887 (d, 3H, J=6.8 Hz).

Example PH

tert-butyl(2S,4S)-2-[5-(2-{(2S)-1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

the title compound was obtained as in example OF (compound tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate)but using (S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid inplace of(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid in step 6.

tert-butyl(2S,4S)-4-(methoxymethyl)-2-(5-{2-[(2S)-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of tert-butyl(2S,4S)-2-[5-(2-{(2S)-1-[(benzyloxy)carbonyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(724 mg, 0.96 mmol) and 70 mg 10% Pd/C in 20 mL ethanol was hydrogenatedat 1 atm overnight. Additional 10% Pd/C (300 mg) and a portion of solidNaHCO3 was added and hydrogenation continued for 4 hours. Filtrationthrough celite and concentration of the filtrate under reduced pressuregave the product as a dark brown solid, 454 mg. Purification by reversephase HPLC gave 65 mg purified product.

methyl{(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A mixture of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (22 mg,0.105 mmol), COMU (45 mg, 0.069 mmol), and tert-butyl(2S,4S)-4-(methoxymethyl)-2-(5-{2-[(2S)-pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(65 mg, 0.105 mmol) in 1.5 mL 10% DIPEA in DMF was stirred for 1.5 h.The reaction mixture was partitioned between ethyl acetate and saturatedsodium bicarbonate. The organic phase was dried over sodium sulphate,filtered and concentrated under reduced pressure. The crude intermediatewas treated with 8 mL 1.25N HCl in ethanol at 50° C. for 4 h. Addedsaturated sodium bicarbonate and extracted the free base intodichloromethane. (106 mg)

methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A mixture of methyl{(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(55 mg, 0.077 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid(14 mg, 0.077 mmol), HATU (32 mg, 0.085 mmol) and 0.4 mL 10% DIPEA inDMF was stirred at room temperature for 1 hour. The product was purifiedby reverse phase HPLC. The product was converted to the free base bydissolution in 2 mL 1:1 acetonitrile:methanol and passage through aprepacked cartridge of polymer supported carbonate. The eluent wasconcentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen,and lyophilized to give the product as a trifluoroacetate salt. (30.7mg): MS (ESI) m/z 869.9 [M+H]⁺.

methyl{(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A mixture of methyl{(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(51 mg, 0.072 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoicacid (14 mg, 0.072 mmol), HATU (30 mg, 0.079 mmol) and 0.4 mL 10% DIPEAin DMF was stirred at room temperature for 1 hour. The product waspurified by reverse phase HPLC. The product was converted to the freebase by dissolution in 2 mL 1:1 acetonitrile:methanol and passagethrough a prepacked cartridge of polymer supported carbonate. The eluentwas concentrated, taken up in 1% TFA in 1:1 acetonitrile:water, frozen,and lyophilized to give the product as a trifluoroacetate salt. (24 mg)

MS (ESI) m/z 885.8 [M+H]⁺;

¹H NMR (CD₃CN) 7.635 (s, 1H), 7.434 (m, 3H), 7.330 (m, 4H), 7.233 (m,1H), 7.164 (m, 1H), 6.983 (m, 1H), 6.747 (m, 2H), 6.127 (m, 1H), 5.584(d, 1H, J=6.4 Hz), 5.431 (m, 1H), 5.145 (m, 1H), 4.729 (s, 2H), 4.442(m, 1H), 4.029 (m, 2H), 3.838 (m, 1H), 3.662-3.534 (m, 2H), 3.572 (s,3H) 3.552 (s, 3H), 3.444-3.310 (m, 3H), 3.240 (s, 3H), 3.225 (s, 3H),2.618 (m, 1H), 2.464 (m, 1H), 2.304 (m, 1H), 2.129 (m, 1H), 2.041 (m,1H), 1.899 (m, 2H), 1.107 (d, 3H, J=6.4 Hz).

Example PI

tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[(benzyloxy)carbonyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

The title compound was obtained as in example OF (compound tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate)but using (2S,5S)-1-(benzyloxycarbonyl)-5-methylpyrrolidine-2-carboxylicacid in place of(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-carboxylicacid.

tert-butyl(2S,4S)-4-(methoxymethyl)-2-(5-{2-[(2S,5S)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

A mixture of the proline (830 mg, 1.08 mmol) and 100 mg 10% Pd/C in 20mL ethanol was hydrogenated at 1 atm overnight. Additional 10% Pd/C (300mg) and a portion of solid NaHCO3 was added and hydrogenation continuedfor 4 hours. Filtration through celite and concentration of the filtrateunder reduced pressure gave the product as a dark brown solid, 722 mg.Purification by reverse phase HPLC gave 100 mg purified product.

methyl{(2S,3R)-3-methoxy-1-[(2S,5S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate

A mixture of tert-butyl(2S,4S)-4-(methoxymethyl)-2-(5-{2-[(2S,5S)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate(101 mg, 0.159 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoicacid (30 mg, 0.159 mmol), HATU (61 mg, 0.159 mmol) and 2 mL 10% DIPEA inDMF was stirred at room temperature for 1.5 hours. Saturated sodiumbicarbonate was added and the product was extracted intodichloromethane, dried over sodium sulphate, filtered and concentratedunder reduced pressure. This crude product was treated with 5 mL 1.25NHCl in ethanol at 50° C. for 4 h and then it was concentrated underreduced pressure. Saturated sodium bicarbonate was added and the productwas extracted into dichloromethane, dried over sodium sulphate, filteredand concentrated under reduced pressure. (74.6 mg)

methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,5S)-1-{(2S,3R)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A mixture of methyl{(2S,3R)-3-methoxy-1-[(2S,5S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate(74.6 mg, 0.105 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoicacid (18.5 mg, 0.105 mmol), HATU (44 mg, 0.116 mmol) and 0.6 mL 10%DIPEA in DMF was stirred at room temperature for 1 hour. The product waspurified by reverse phase HPLC. (48.1 mg)

MS (ESI) m/z 866.1 [M+H]⁺.

Example PJ

tert-butyl(2S,4S)-2-(9-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(trifluoromethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

the title compound was prepared as in example OF for compound tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate,by using(2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid in place of(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid and(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid in place of(2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylicacid.

methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(trifluoromethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

tert-butyl(2S,4S)-2-(9-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(trifluoromethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (<0.412 mmol, crude from previous step) wastreated with 6 mL 4N HCl in dioxane at room temperature overnight andthen at 50° C. for 1 hour. Diethyl ether (20 mL) was added and theprecipitate of hydrochloride salt was collected by vacuum filtration.(126 mg, 0.16 mmol). This material was combined with(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (34 mg, 0.16 mmol),COMU (70 mg, 0.16 mmol), and 1.6 mL of 10% DIPEA in DMF. After 1 hour atroom temperature, the mixture was added dropwise into 25 mL saturatedsodium bicarbonate, with stirring and the resulting precipitate wascollected by vacuum filtration and washed with 2 mL water. The productwas purified, then re-purified by reverse phase HPLC. (3.5 mg).

MS (ESI) m/z 938.1 [M+H]⁺.

Example PK

(2S,4S)-tert-butyl 2-formyl-4-methylpyrrolidine-1-carboxylate

A mixture of(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid(5.2g, 22.7 mmol), O,N-dimethylhydroxylamine hydrochloride (2.4g, 24.9mmol), HATU (10.4g, 27.2 mmol) and DIPEA (9.5 mL, 54.5 mmol) in 114 mLDMF was stirred at room temperature overnight. The mixture was extractedinto ethyl acetate and washed with saturated bicarbonate and water,dried over sodium sulphate, filtered, and concentrated. It was thendissolved in diethyl ether (100 mL) and washed with water to removeresidual DMF, dried, filtered, and concentrated to a pale yellow oil(5.30g, 19.5 mmol) of (2S,4S)-tert-butyl2-(methoxy(methyl)carbamoyl)-4-methylpyrrolidine-1-carboxylate.

(2S,4S)-tert-butyl2-(methoxy(methyl)carbamoyl)-4-methylpyrrolidine-1-carboxylate (5.30g,19.5 mmol) was dissolved in 120 mL THF, cooled to −78° C. and treatedwith lithium aluminium hydride (1M in THF, 19.5 mL, 19.5 mmol) dropwisevia addition funnel. After 1 hour, the mixture was brought to 0° C. andkept at that temperature for 2 hours. It was quenched by dropwiseaddition of a 50 mL solution of 3.0g KHSO4 in water, removed from theice bath, and stirred 15 minutes at room temperature. The product wasextracted with three 75 mL portions of ethyl acetate and washed withbrine. The organic phase was dried over sodium sulphate, filtered, andconcentrated to give crude (2S,4S)-tert-butyl2-formyl-4-methylpyrrolidine-1-carboxylate. (4.89g)

(2S,4S)-tert-butyl2-(1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

To a solution of (2S,4S)-tert-butyl2-formyl-4-methylpyrrolidine-1-carboxylate (4.89 g, 22.9 mmol), ammoniumhydroxide (17 mL) and water (17 mL) was added, dropwise, glyoxal (40% inwater, 14.6 mL, 128 mmol) and the resulting mixture was stirred at roomtemperature overnight. Saturated sodium bicarbonate (100 mL) was addedand the mixture was extracted with four 75 mL portions ofdichloromethane. The organic phase was washed with water, dried oversodium sulphate, filtered and concentrated, and then purified by silicagel chromatography to give a total of 3.76g product.

(2S,4S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate

A mixture of (2S,4S)-tert-butyl2-(1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (1.0g, 3.97mmol), iodine (2.22g, 8.75 mmol) and sodium carbonate (1.3g, 12.31 mmol)in 20 mL dioxane and 13.25 mL water was covered in foil and stirred atroom temperature overnight. The mixture was diluted with ethyl acetateand treated with 10% sodium thiosulfate (5 mL) and stirred for 10minutes. The organic phase was washed with brine, and then the aqueousphase was back extracted with ethyl acetate. The combined organic phaseswere dried over sodium sulphate, filtered and concentrated to providecrude (2S,4S)-tert-butyl2-(4,5-diiodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(2.25g) as a pale yellow solid.

A solution of (2S,4S)-tert-butyl2-(4,5-diiodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate(2.25g, 4.4 mmol) in 18 mL ethanol and 18 mL water was treated withsodium sulfite (5.59g, 44.4 mmol) and heated at 90° C. overnight. Themixture was partitioned between ethyl acetate and water. The aqueousphase was extracted with more ethyl acetate and the combined organicphase was washed with brine, dried over sodium sulphate, filtered,concentrated, and purified by silica gel chromatography to give 766 mg(2S,4S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate.

Example PL

(2S,3aS,6aS)-2-benzyl 1-tert-butylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

To a solution of commercially available (2S,3aS,6aS)-2-benzyl1-tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (4.70g, 16.68 mmol) in methylene chloride (42 mL) was added Di-tert-butyldicarbonate (7.28 g, 33.36 mmol) N,N-diisopropylethylamine (5.82 mL,33.36 mmol) and 4-(Dimethylamino)pyridine (0.20 g, 1.67 mmol). Thesolution was stirred under air for 16 hours. Upon completion, thereaction was concentrated in vacuo, diluted in ethyl acetate, and washedwith 1N HCl. The aqueous layers were backextracted twice with ethylacetate and the combined organic layers were dried over sodium sulfate,filtered and concentrated. The resulting residue was purified by silicagel chromatography (5-40% ethyl acetate in hexanes) to afford(2S,3aS,6aS)-2-benzyl 1-tert-butylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate which was usedwithout further purification. MS (ESI) m/z 368.47 [M+Na]⁺.

(2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylicacid

To a 250 mL round bottom flask charged with a stirbar and(2S,3aS,6aS)-2-benzyl 1-tert-butylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (5.76 g, 16.68 mmol)was added 10% Palladium on carbon (1.77g). Ethanol was poured over themixture and the reaction mixture was evacuated and flushed with hydrogengas three times. The suspension was stirred at room temperature underand atmosphere of hydrogen for 24 hours. Upon completion, the reactionmixture was filtered through celite and concentrated to give(2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylicacid (4.45g, >99%). MS (ESI) m/z 256.21 [M+H]⁺.

Example PM

tert-butyl2-[5-(2-{(2S,3aS,6aS)-1-[N-(methoxycarbonyl)-1-valyl]octahydrocyclopenta[b]pyrrol-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

This compound was made in an analogous manner to tert-butyl(2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylatesubstituting (2S,3aS,6aS)-1-(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylicacid for the initial alkylation of9-bromo-3-chloro-10,11-dihydro-6H-naphtho[2,3-c]chromen-8(9H)-one.Reactions in the synthesis of tert-butyl2-[5-(2-{(2S,3aS,6aS)-1-[N-(methoxycarbonyl)-L-valyl]octahydrocyclopenta[b]pyrrol-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylategave similar product yields as in the synthesis of tert-butyl(2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate.MS (ESI) m/z 774.1 [M+H]⁺.

Example PN

methyl{(1R)-2-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

To a solution of tert-butyl2-[5-(2-{(2S,3aS,6aS)-1-[N-(methoxycarbonyl)-L-valyl]octahydrocyclopenta[b]pyrrol-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(0.128 g, 0.165 mmol) in a mixture of CH₂Cl₂ (1.6 mL) and MeOH (0.33 mL)was added HCl (4M in 1,4-dioxane, 1.24 mL, 4.9 mmol). The solution wasstirred at room temperature for 1.5 h and concentrated to dryness.

The intermediate was dissolved in CH₂Cl₂ (1.6 mL).(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.052 g, 0.25 mmol)and DIPEA (0.087 mL, 0.496 mmol) were then added to the solution. Thereaction mixture was cooled to −40° C. (external temperature,MeCN/CO₂(s) bath). COMU (0.113 g, 0.265 mmol) was then added andsolution was allowed to warm to 0° C. over 1.5 h. Upon completion byLCMS, the solution was diluted with DMF and concentrated. The crudeproduct was purified by preparative HPLC (Gemini column, 10-47% MeCN/H₂Owith 0.1% TFA) and the desired fractions were combined. The solution wasconcentrated until the aqueous layer remained and aqueous bicarbonate(sat.) was slowly added until the solution was basic. The resultingslurry was stirred at room temperature for 2 h and filtered. Theresulting solid was dried in vacuo to provide methyl{(1R)-2-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(0.068 g, 48%).

MS (ESI) m/z 865.7 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.44-8.30 (m, 1H),8.02-7.82 (m, 2H), 7.81-7.58 (m, 4H), 7.50-7.11 (m, 6H), 7.09-6.83 (m,2H), 5.72-5.45 (m, 2H), 5.41 (s, 1H), 5.34-5.28 (m, 1H), 5.22 (s, 3H),4.69-4.64 (m, 1H), 4.26-4.19 (m, 1H), 4.03-3.98 (m, 1H), 3.96-3.91 (m,1H), 3.66 (d, 4H), 2.98-2.91 (m, 1H), 2.88-2.83 (m, 1H), 2.58-2.48 (m,1H), 2.27-2.12 (m, 4H), 2.11-2.00 (m, 3H), 2.00-1.89 (m, 2H), 1.77-1.72(m, 1H), 1.31-1.04 (m, 3H), 0.93 (d, 6H).

Example PO

methyl{(2S)-1-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To a solution of tert-butyl2-[5-(2-{(2S,3aS,6aS)-1-[N-(methoxycarbonyl)-L-valyl]octahydrocyclopenta[b]pyrrol-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate(0.030 g, 0.039 mmol) in a mixture of CH₂Cl₂ (0.39 mL) and MeOH (0.078mL) was added HCl (4M in 1,4-dioxane, 0.29 mL, 1.16 mmol). The solutionwas stirred at room temperature for 1.5 h and concentrated to dryness.

The intermediate was dissolved in CH₂Cl₂ (0.39 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.007 g, 0.043 mmol)and DIPEA (0.020 mL, 0.116 mmol) were then added to the solution. HATU(0.018 g, 0.047 mmol) was added and solution was allowed to stir at roomtemp. Upon completion, the solution was diluted with DMF andconcentrated. The crude product was purified by preparative HPLC (Geminicolumn, 10-47% MeCN/H₂O with 0.1% TFA) and the desired fractions werecombined and lyophilized to provide methyl{(2S)-1-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.010g, 31%). MS (ESI) m/z 832.2 [M+H]⁺.

Example PP

methyl[(1S)-2-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate

methyl [(1S)-2-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate:This compound was made in an analogous manner to methyl{(2S)-1-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate,substituting(S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid to give methyl[(1S)-2-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate(0.039, 56%). MS (ESI) m/z 874.34 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.58(s, 2H), 8.26-8.08 (m, 2H), 7.96-7.75 (m, 4H), 7.65-7.54 (m, 5H),5.36-5.11 (m, 4H), 4.34-4.04 (m, 4H), 3.97-3.79 (m, 4H), 3.65 (s, 4H),3.53-3.44 (m, 2H), 2.68-2.47 (m, 4H), 2.32-2.02 (m, 7H), 1.95-1.82 (m,3H), 1.77-1.54 (m, 4H), 1.49-1.24 (m, 5H), 1.10-0.99 (m, 3H), 0.92-0.85(m, 4H).

Example PQ

tert-butyl2-[5-(2-{(2S,4S)-4-[(difluoromethoxy)methyl]-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate

This compound was made in an analogous manner to tert-butyl2-[5-(2-{(2S,3aS,6aS)-1-[N-(methoxycarbonyl)-L-valyl]octahydrocyclopenta[b]pyrrol-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylatesubstituting(2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylicacid for the initial alkylation of9-bromo-3-chloro-10,11-dihydro-6H-naphtho[2,3-c]chromen-8(9H)-one.Reactions in the synthesis of tert-butyl2-[5-(2-{(2S,4S)-4-[(difluoromethoxy)methyl]-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylategave similar product yields as in the synthesis of tert-butyl2-[5-(2-{(2S,3aS,6aS)-1-[N-(methoxycarbonyl)-L-valyl]octahydrocyclopenta[b]pyrrol-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate.MS (ESI) m/z 815.04 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.58 (s, 1H), 8.18(d, 1H), 7.96-7.85 (m, 3H), 7.70 (s, 1H), 7.60 (d, 1H), 7.50-7.38 (m,4H), 7.10 (s, 1H), 6.46 (t, 1H), 5.51 (s, 1H), 5.39-5.36 (m, 1H),5.31-5.28 (m, 21-), 4.43-4.36 (m, 1H), 4.24 (d, 1H), 4.13-4.02 (m, 3H),3.75-3.62 (m, 7H), 3.51-3.47 (m, 1H), 3.18-3.11 (m, 2H), 2.93-2.83 (m,2H), 2.75-2.69 (m, 1H), 2.47-2.36 (m, 2H), 2.23-2.09 (m, 3H), 2.01-1.94(m, 2H), 0.87 (dd, 6H).

Example PR

tert-butyl(2S,4S)-2-[5-(2-{(1R,3S,5R)-2-[N-(methoxycarbonyl)-L-valyl]-2-azabicyclo[3.1.0]hex-3-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

This compound was made in an analogous manner to tert-butyl(2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylatesubstituting(1R,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid for the initial alkylation of9-bromo-3-chloro-10,11-dihydro-6H-naphtho[2,3-c]chromen-8(9H)-one, andsubstituting (2S,4S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylatefor the Suzuki-Miyara couping. Reactions in the synthesis of tert-butyl(2S,4S)-2-[5-(2-{(1R,3S,5R)-2-[N-(methoxycarbonyl)-L-valyl]-2-azabicyclo[3.1.0]hex-3-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylategave similar product yields as in the synthesis of tert-butyl(2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate.MS (ESI) m/z 791.0 [M+H]⁺.

methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(1R,3S,5R)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

To a solution of tert-butyl (2S,4S)-2-[5-(2-{(1R,3S,5R)-2-[N-(methoxycarbonyl)-L-valyl]-2-azabicyclo[3.1.0]hex-3-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.060 g, 0.076 mmol) in a mixture of CH₂Cl₂ (0.76 mL) and MeOH (0.15mL) was added HCl (4M in 1,4-dioxane, 0.570 mL, 2.28 mmol). The solutionwas stirred at room temperature for 2 h and concentrated to dryness. Theintermediate was dissolved in CH₂Cl₂ (0.76 mL).(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (0.024 g, 0.114 mmol)and DIPEA (0.040 mL, 0.228 mmol) were then added to the solution. Thereaction mixture was cooled to −40° C. (external temperature,MeCN/CO₂(s) bath). COMU (0.052 g, 0.122 mmol) was then added andsolution was allowed to warm to 0° C. over 1.5 h. Upon completion byLCMS, the solution was diluted with DMF and concentrated. The crudeproduct was purified by preparative HPLC (Gemini column, 10-45% MeCN/H₂Owith 0.1% TFA) and lyophilized to provide methyl{(1R)-2-[(2S,4S)-2-(5-{2-[(1R,3S,5R)-2-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-azabicyclo[3.1.0]hex-3-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate(0.028 g, 42%). MS (ESI) m/z 881.8 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.45-8.33 (m, 1H), 8.02-7.94 (m, 1H), 7.91-7.75 (m, 2H), 7.72-7.67 (m,1H), 7.61 (s, 1H), 7.59-7.34 (m, 6H), 7.09-6.91 (m, 2H), 5.62-5.38 (m,2H), 5.29 (t, 1H), 5.24-5.09 (m, 3H), 4.61 (d, 1H), 4.37-4.26 (m, 1H),3.83-3.73 (m, 1H), 3.69-3.56 (m, 6H), 3.50-3.40 (m, 1H), 3.20-3.11 (m,1H), 2.99 (s, 1H), 2.83 (d, 1H), 2.63-2.50 (m, 2H), 2.47-2.34 (m, 2H),2.29-2.13 (m, 2H), 2.10-1.95 (m, 2H), 1.37-1.23 (m, 3H), 1.19-1.10 (m,1H), 1.03-0.78 (m, 7H).

Example PS

tert-butyl(2S,4S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-[(difluoromethoxy)methyl]pyrrolidine-1-carboxylate

This compound was made in an analogous manner to tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatesubstituting(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acidfor the initial alkylation of3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, andsubstituting(2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylicacid for the other alkylation in the sequence. Reactions in thesynthesis of tert-butyl(2S,4S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-[(difluoromethoxy)methyl]pyrrolidine-1-carboxylategave similar product yields as in the synthesis of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 772.03 [M+H]⁺.

methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-4-[(difluoromethoxy)methyl]-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To a solution of tert-butyl(2S,4S)-2-(9-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-[(difluoromethoxy)methyl]pyrrolidine-1-carboxylate(0.081 g, 0.105 mmol) in a mixture of CH₂Cl₂ (1.05 mL) and MeOH (0.210mL) was added HCl (4M in 1,4-dioxane, 0.788 mL, 3.15 mmol). The solutionwas stirred at room temperature for 2 h and concentrated to dryness. Theintermediate was dissolved in CH₂Cl₂ (1.05 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.040 g, 0.231 mmol)and DIPEA (0.055 mL, 0.315 mmol) were then added to the solution. HATU(0.176 g, 0.462 mmol) was added and solution was allowed to stir at roomtemp. Upon completion, the solution was diluted with DMF andconcentrated. The crude product was purified by preparative HPLC (Geminicolumn, 10-45% MeCN/H₂O with 0.1% TFA) and the desired fractions werecombined. The solution was concentrated until the aqueous layer remainedand aqueous bicarbonate (sat.) was slowly added until the solution wasbasic. The resulting slurry was stirred at room temperature for 2 h andfiltered. The resulting solid was dried in vacuo to provide methyl{(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-4-[(difluoromethoxy)methyl]-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.025 g, 27%). MS (ESI) m/z 886.1 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.49-8.25 (m, 2H), 8.08-7.82 (m, 2H), 7.79-7.27 (m, 5H), 6.45 (t, 1H),5.36-5.26 (m, 1H), 5.22-5.07 (m, 3H), 4.78-4.49 (m, 2H), 4.45-4.19 (m,3H), 4.16-4.05 (m, 2H), 3.99-3.92 (m, 1H), 3.85-3.71 (m, 2H), 3.66 (s,3H), 2.88-2.70 (m, 2H), 2.69-2.49 (m, 2H), 2.42-2.26 (m, 2H), 2.23-2.10(m, 2H), 2.07-1.87 (m, 3H), 1.51 (d, 2H), 1.34-1.20 (m, 2H), 1.17-0.76(m, 12H).

Example PT

tert-Butyl(2S,4S)-2-(5-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-[(difluoromethoxy)methyl]pyrrolidine-1-carboxylate

This compound was made in an analogous manner to tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatesubstituting(2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylicacid for the initial alkylation of3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, andsubstituting(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acidfor the other alkylation in the sequence. Reactions in the synthesis oftert-butyl(2S,4S)-2-(5-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-[(difluoromethoxy)methyl]pyrrolidine-1-carboxylategave similar product yields as in the synthesis of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 772.31 [M+H]⁺.

methyl{(2S)-1-[(2S,4S)-4-[(difluoromethoxy)methyl]-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To tert-butyl(2S,4S)-2-(5-{2-[(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-[(difluoromethoxy)methyl]pyrrolidine-1-carboxylate(0.057 g, 0.074 mmol) in a mixture of CH₂Cl₂ (0.739 mL) and MeOH (0.148mL) was added HCl (4M in 1,4-dioxane, 0.555 mL, 2.218 mmol). Thesolution was stirred at room temperature for 2 h and concentrated todryness.

The intermediate was dissolved in CH₂Cl₂ (0.739 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.028 g, 0.163 mmol)and DIPEA (0.039 mL, 0.222 mmol) were then added to the solution. HATU(0.124 g, 0.325 mmol) was added and solution was allowed to stir at roomtemp. Upon completion, the solution was diluted with DMF andconcentrated. The crude product was purified by preparative HPLC (Geminicolumn, 10-46% MeCN/H₂O with 0.1% TFA) and the desired fractions werecombined and lyophilized to provide methyl{(2S)-1-[(2S,4S)-4-[(difluoromethoxy)methyl]-2-(5-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.011 g, 17%). MS (ESI) m/z 886.1 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.67-8.51 (m, 1H), 8.26-8.11 (m, 1H), 8.04-7.75 (m, 3H), 7.69-7.58 (m,2H), 6.43 (t, 1H), 5.41-5.15 (m, 4H), 4.48-3.90 (m, 6H), 3.82 (s, 1H),3.71-3.57 (m, 5H), 3.53-3.43 (m, 1H), 3.20-3.01 (m, 2H), 2.92-2.63 (m,3H), 2.60-2.25 (m, 4H), 2.15-1.86 (m, 4H), 1.57 (d, 3H), 1.24 (d, 2H),1.07 (dd, 2H), 0.98-0.77 (m, 9H).

Example PU

tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-(tert-butoxycarbonyl)-4-[(difluoromethoxy)methyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

This compound was made in an analogous manner to tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylatesubstituting(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid for the initial alkylation of3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, andsubstituting(2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylicacid for the other alkylation in the sequence. Reactions in thesynthesis of tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-(tert-butoxycarbonyl)-4-[(difluoromethoxy)methyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylategave similar product yields as in the synthesis of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate.MS (ESI) m/z 801.1 [M+H]⁺.

methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-4-[(difluoromethoxy)methyl]-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To tert-butyl(2S,4S)-2-[5-(2-{(2S,4S)-1-(tert-butoxycarbonyl)-4-[(difluoromethoxy)methyl]pyrrolidin-2-yl}-1,11dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(0.092 g, 0.115 mmol) in a mixture of CH₂Cl₂ (1.15 mL) and MeOH (0.230mL) was added HCl (4M in 1,4-dioxane, 0.862 mL, 3.446 mmol). Thesolution was stirred at room temperature for 2 h and concentrated todryness.

The intermediate was dissolved in CH₂Cl₂ (1.149 mL).(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.044 g, 0.253 mmol)and DIPEA (0.060 mL, 0.345 mmol) were then added to the solution. HATU(0.192 g, 0.505 mmol) was added and solution was allowed to stir at roomtemp. Upon completion, the solution was diluted with DMF andconcentrated. The crude product was purified by preparative HPLC (Geminicolumn, 10-45% MeCN/H₂O with 0.1% TFA) and the desired fractions werecombined. The solution was concentrated until the aqueous layer remainedand aqueous bicarbonate (sat.) was slowly added until the solution wasbasic. The resulting slurry was stirred at room temperature for 2 h andfiltered. The resulting solid was dried in vacuo to provide methyl{(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-4-[(difluoromethoxy)methyl]-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(0.042 g, 40%). MS (ESI) m/z 916.30 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.55-8.25 (m, 1H), 8.15-7.85 (m, 2H), 7.83-7.26 (m, 5H), 6.44 (t, 1H),5.37-5.02 (m, 4H), 4.47-4.35 (m, 1H), 4.33-4.18 (m, 3H), 4.15-3.90 (m,3H), 3.81-3.45 (m, 11H), 3.39 (s, 3H), 2.90-2.27 (m, 5H), 2.22-1.92 (m,4H), 1.12-0.73 (m, 13H).

Example PV

methyl(S)-1-((S)-2-(2′-((2S,4S)-1-((R)-2-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-((difluoromethoxy)methyl)pyrrolidin-2-yl)-1H,1′H-7,7′-1-binaphtho[2,1-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

This compound was made using a similar procedure as was used to makemethyl (R)-2-((2S,4S)-4-(methoxymethyl)-2-(2′-((1R,3S,5R)-2-((S)-3-methyl-2-methoxycarbonylaminobutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate,using methyl(S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamateand (2R,4S)-tert-butyl2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-4-((difluoromethoxy)methyl)pyrrolidine-1-carboxylatein the Suzuki-Miyaura cross coupling to give methyl(S)-1-((S)-2-(2′-((2S,4S)-1-((R)-2-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-((difluoromethoxy)methyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[2,1-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(0.203g, 56%). MS (ESI) m/z 944.10 [M+H]⁺.

methyl(S)-1-((S)-2-(2′-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-((difluoromethoxy)methyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[2,1-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1oxobutan-2-ylcarbamate

To a solution of methyl(S)-1-((S)-2-(2′-((2S,4S)-1-((R)-2-(tert-butoxycarbonylamino)-2-phenylacetyl)-4-((difluoromethoxy)methyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[2,1-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(0.203g, 0.215 mmol) in a mixture of DCM (2.15 mL) and MeOH (0.43 mL)was added HCl (2.15 mL, 4N in 1,4-dioxane, 8.6 mmol). The reaction wasstirred at room temp for 30 minutes. Upon completion, the crude reactionmixture was concentrated in vacuuo.

The residue was dissolved in DMF (2.15 mL). DIPEA (0.15 mL, 0.861 mmol),propane carboxylic acid (0.020 mL, 0.258 mmol), and HATU (0.123g, 0.323mmol). Upon completion, the reaction mixture was filtered through asyringe filter, the crude product was purified by preparative HPLC(Gemini column, 10-52% MeCN/H₂O with 0.1% TFA) and the desired fractionswere combined. The solution was concentrated until the aqueous layerremained and aqueous bicarbonate (sat.) was slowly added until thesolution was basic. The resulting slurry was stirred at room temperaturefor 2 h and filtered. The resulting solid was dried in vacuo to providemethyl(S)-1-((S)-2-(2′-((2S,4S)-1-((R)-2-(cyclopropanecarboxamido)-2-phenylacetyl)-4-((difluoromethoxy)methyl)pyrrolidin-2-yl)-1H,1′H-7,7′-binaphtho[2,1-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1oxobutan-2-ylcarbamate (0.098 g, 50%). MS (ESI) m/z 911.7 [M+H]⁺. ¹H NMR(400 MHz, cd₃od) δ 8.68-8.50 (m, 2H), 8.42-8.23 (m, 2H), 8.14-7.90 (m,2H), 7.86-7.67 (m, 3H), 7.62-7.51 (m, J=6.2 Hz, 2H), 7.49-7.39 (m,J=15.3, 7.6 Hz, 2H), 6.86-6.01 (m, 5H), 5.83-5.67 (m, 1H), 5.59 (s, 1H),5.49-5.33 (m, 2H), 4.64-4.18 (m, 3H), 4.13-3.92 (m, 2H), 3.87-3.76 (m,J=7.2 Hz, 2H), 3.68 (s, 2H), 2.89-2.22 (m, 7H), 2.19-2.00 (m, 3H),1.77-1.48 (m, 2H), 1.11-0.85 (m, 7H), 0.80-0.68 (m, J=4.5 Hz, 2H).

Example PW

methyl(S)-1-((2S,4S)-2-(2′-((1R,3S,5R)-2-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[2,1-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

This compound was made using the same procedure as was used to makemethyl (R)-2-((2S,4S)-4-(methoxymethyl)-2-(2′-((1R,3 S,5R)-2-((S)-3-methyl-2-methoxycarbonylaminobutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate,using methyl(S)-1-((2S,4S)-4-(methoxymethyl)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateand (1R,3 S,5R)-tert-butyl3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylatein the Suzuki-Miyaura cross coupling to give methyl(S)-1-((2S,4S)-2-(2′-((1R,3S,5R)-2-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[2,1-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(0.048g, 27%). MS (ESI) m/z 877.71 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.68-8.50 (m, 2H), 8.42-8.23 (m, 2H), 8.14-7.90 (m, 2H), 7.86-7.67 (m,3H), 7.62-7.51 (m, J=6.2 Hz, 2H), 7.49-7.39 (m, J=15.3, 7.6 Hz, 2H),6.86-6.01 (m, 5H), 5.83-5.67 (m, 1H), 5.59 (s, 1H), 5.49-5.33 (m, 2H),4.64-4.18 (m, 3H), 4.13-3.92 (m, 2H), 3.87-3.76 (m, J=7.2 Hz, 2H), 3.68(s, 2H), 2.89-2.22 (m, 7H), 2.19-2.00 (m, 3H), 1.77-1.48 (m, 2H),1.11-0.85 (m, 7H), 0.80-0.68 (m, J=4.5 Hz, 2H).

Example PX

(2S,4S)-1-tert-butyl 2-methyl4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate

A 100 mL round-bottom flask was charged with (2S,4S)-1-tert-butyl2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.33 g, 12.84mmol), CuI (0.489 g, 2.56 mmol), and anhydrous acetonitrile (57.1 mL).The reaction was heated to 45° C. (ext. oil bath).2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.655 mL, 25.68 mmol) wasadded at 45° C. over 30 minutes via syringe pump. The reaction washeated for 30 minutes. Upon completion as monitored by TLC, the reactionmixture was cooled to room temperature and concentrated in vacuo. Thecrude residue was diluted in EtOAc and washed with sodium bicarbonate(aq). The bicarbonate layer was back extracted with ethyl acetate twice.Combined organic layers were washed with brine, dried over sodiumsulphate, filtered and concentrated. The resulting residue was furtherpurified via silica gel chromatography (10 to 40% EtOAc/Hexanes) toafford (2S,4S)-1-tert-butyl 2-methyl4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 61%).MS (ESI) m/z 210.21 [M+H-Boc]⁺.

(2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylicacid

To a solution of (2S,4S)-1-tert-butyl 2-methyl4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 7.79mmol) in a mixture of THF (39 mL) and MeOH (15.6 mL) was added LiOH (2.5M aqueous, 15.6 mL, 38.9 mmol). The resulting solution was stirred atroom temperature for 1 h. Upon completion by TLC the reaction mixturewas and acidified with aqueous HCl (1N). The desired product wasextracted with CH₂Cl₂ (3×). The combined organic layers were dried overNa₂SO₄ and concentrated to provide(2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylicacid (2.4 g, 99%). MS (ESI) m/z 294.96 [M−H]⁻. ¹H-NMR: 400 MHz,(acetone-d₆) δ (mixture of rotomers): 6.50 (t, 1H), 4.36-4.17 (m, 1H),3.93 (d, 2H), 3.77-3.67 (m, 1H), 3.63-3.59 (m, 1H), 3.26-3.12 (m, 1H),2.72-2.41 (m, 2H), 1.89-1.73 (m, 2H), 1.41 (s, 9H).

Example PY

Methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A solution of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(150 mg, 0.19 mmol) in 1.25 N HCl in EtOH (3 mL) was stirred overnightthen heated to 50° C. for 3 h. The reaction was concentrated and thecrude material dissolved in DMF (2 mL). To this solution was added asolution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (52 mg,0.25 mmol) and COMU (90 mg, 0.21 mmol). To the resulting solution wasadded diisopropylethylamine (0.099 mL, 0.57 mmol). After stirring for 2h at room temperature, the reaction was quenched with 1N HCl (0.200 mL)and purified by HPLC. After lyophilization, the TFA salt was dissolvedin EtOAc and washed with saturated NaHCO₃. The organic phase was driedover Na₂SO₄ and concentrated. The free base was then dissolved inMeCN/H₂O and lyophilized to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(65 mg, 39%). LCMS-ESI⁺: calculated for C₄₉H₅₄N₈O₈: 882.4; observed[M+1]⁺: 884.1. Diagnostic peaks in NMR¹H NMR (CD₃OD): 8.28 (s, 1H), 8.21(s, 1H), 8.04 (s, 1H), 7.91-7.01 (m, 10H), 3.62 (s, 3H), 3.34 (s, 3H),3.23 (s, 3H), 1.56 (d, 3H), 1.03 (d, 3H), 0.94 (d, 3H).

Example PZ

Methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-[5-(2-({(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(100 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C.for 3 h and then concentrated under reduced pressure. The crude residuewas treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (34mg, 0.20 mmol), HATU (54 mg, 0.14 mmol) and DMF (1.3 mL), thenN-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 h,the mixture was quenched with 1N HCl (0.100 mL) and then purified byHPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(91 mg, 82%).

LCMS-ESI⁺: calculated for C₄₆H₅₆N₈O₈: 848.4. observed [M+1]⁺: 850.2.

Example QA

Methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(119 mg, 0.15 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C.for 3 h and then concentrated under reduced pressure. The crude residuewas treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid(43 mg, 0.23 mmol), HATU (63 mg, 0.17 mmol) and DMF (2 mL), thenN-methylmorpholine (0.050 mL, 0.45 mmol) was added dropwise. After 3 hr,the mixture was quenched with 1N HCl (0.100 mL) and then purified byHPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(76 mg, 59%).

LCMS-ESI⁺: calculated for C₄₆H₅₆N₈O₉: 864.4. observed [M+1]⁺: 866.1.

Example QB

Methyl(2S,3S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate

(2S,4S)-tert-butyl2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (100 mg,0.13 mmol) in 1.25 N HCl in EtOH (15 mL) was heated to 50° C. for 3 hand then concentrated under reduced pressure. The crude residue wastreated with (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid(625 mg, 3.30 mmol), HATU (1.05 g, 2.77 mmol) and DMF (10 mL), thenDIPEA (1.33 mL, 7.62 mmol) was added dropwise. After 2 h, the mixturewas poured into saturated aqueous NaHCO₃ and then extracted with EtOAc.The organic phase was washed with successively with 5% aqueous LiCl andBrine. The organics were dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (30 to 90% of 10% MeOH/EtoAc to Hexanes) afforded methyl(2S,3S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate(932 mg, 81%).

Tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-1-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate

(2S,4S)-Tert-butyl4-(methoxymethyl)-2-(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(856 mg, 1.4 mmol), methyl(2S,3S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate(932 mg, 2.1 mmol), Pd(PPh₃)₄ (162 mg, 0.14 mmol), PdCl₂(dppf)₂ (102 mg,0.14 mmol), and K₂CO₃ (2M in H₂O, 2.31 mL, 4.62 mmol) were combined inDMSO (8 mL) and dioxanes (8 mL). The mixture was degassed with bubblingArgon for 10 min the heated to 95° C. for 1 h. After cooling, thereaction mixture was diluted with EtOAc, and washed successively withsaturated aqueous NaHCO₃ and brine. The organics were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by silica column chromatography (1% to 20% MeOH/EtOAc) toafford tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-1-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(701 mg, 62%).

Methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate

A solution of tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-1-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(218 mg, 0.27 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C.for 3 h. The reaction was concentrated and the crude material dissolvedin DMF (3 mL). To this solution was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (73 mg, 0.35 mmol) andCOMU (127 mg, 0.30 mmol). To the resulting solution was addeddiisopropylethylamine (0.141 mL, 0.81 mmol). After stirring for 2 h atroom temperature, the reaction was quenched with 1N HCl (0.200 mL) andpurified by HPLC. After lyophilization, the TFA salt was dissolved inEtOAc and washed with saturated NaHCO₃. The organic phase was dried overNa₂SO₄ and concentrated. The free base was then dissolved in MeCN/H₂Oand lyophilized to afford methyl{(1R)-2-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate:(121 mg, 50%). LCMS-ESI⁺: calculated for C₅₀H₅₆N₈O₈: 896.4. observed[M+1]⁺: 897.5.

Example QC

Methyl{(2S)-1-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-1-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C.for 3 h and then concentrated under reduced pressure. The crude residuewas treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (32mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), thenN-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 h,the mixture was quenched with 1N HCl (0.100 mL) and then purified byHPLC to afford methyl{(2S)-1-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(80 mg, 71%).

LCMS-ESI⁺: calculated for C₄₇H₅₈N₈O₈: 862.4. observed [M+1]⁺: 864.2.

Example QD

Methyl{(2S,3R)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-1-allothreonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate

tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-1-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C.for 3 h and then concentrated under reduced pressure. The crude residuewas treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid(35 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), thenN-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 hr,the mixture was quenched with 1N HCl (0.100 mL) and then purified byHPLC to afford methyl{(2S,3R)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-1-allothreonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate(92 mg, 81%).

LCMS-ESI⁺: calculated for C₄₇H₅₈N₈O₉: 878.4. observed [M+1]⁺: 879.3.

Example QE

Methyl{(3R)-1-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate

tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-1-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate(105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C.for 3 h and then concentrated under reduced pressure. The crude residuewas treated with (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid(34 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), thenN-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 h,the mixture was quenched with 1N HCl (0.100 mL) and then purified byHPLC to afford methyl{(3R)-1-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate(98 mg, 86%).

LCMS-ESI⁺: calculated for C₄₈H₆₀N₈O₈: 876.5. observed [M+1]⁺: 878.2.

Example QF

(2S,5S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)5-methylpyrrolidine-1,2-dicarboxylate

To a solution of9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.41 g,3.88 mmol) in MeCN (17 mL) was added(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(980 mg, 4.27 mmol) and DIPEA (1.49 mL, 8.54 mmol). After stirring for18 h at 50° C., the solution was diluted with EtOAc and washedsuccessively with 1N HCl, saturated aqueous NaHCO₃ and brine. Theorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(10% to 30% EtOAc/hexanes) to afford (2S,5S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)5-methylpyrrolidine-1,2-dicarboxylate (1.63 g, 81%).

(2S,5S)-tert-butyl2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-5-(methyl)pyrrolidine-1-carboxylate

(2S,5S)-1-tert-butyl2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl)5-methylpyrrolidine-1,2-dicarboxylate (1.63 g, 3.18 mmol) was addedtoluene (30 mL), 2-methoxyethanol (3 mL), and ammonium acetate (3.68 g,77.1 mmol) and the solution was heated to reflux overnight. Thefollowing morning, the solution was cooled to rt and was diluted withEtOAc and washed successively with water, saturated aqueous NaHCO₃ andbrine. The organics were dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The crude residue was purified by silica columnchromatography (40% to 80% EtOAc/hexanes) to afford (2S,5S)-tert-butyl2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(1.13 g, 72%).

((2S,5S)-tert-butyl2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate

To a solution of (2S,5S)-tert-butyl2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-5-(methyl)pyrrolidine-1-carboxylate(1.13 g, 2.3 mmol) in CH₂Cl₂ (25 mL) was added MnO₂ (9.98 g, 115 mmol).The reaction mixture was stirred overnight then filtered over celite.The filter cake was washed with copious CH₂Cl₂ and MeOH, and thefiltrate was concentrated under reduced pressure to afford the crudeproduct (2S,5S)-tert-butyl2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(931 mg, 83%).

Methyl{(2S)-1-[(2S,5S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

(2S,5S)-tert-butyl2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate(931 mg, 1.9 mmol) in 1.25 N HCl in EtOH (8 mL) was heated to 50° C. for3 h and then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (499 mg,2.9 mmol), HATU (795 mg, 2.1 mmol) and DMF (10 mL), thenN-methylmorpholine (0.627 mL, 5.7 mmol) was added dropwise. Afterstirring for 1 h, the reaction was diluted with EtOAc and washedsuccessively with saturated aqueous NaHCO₃, 5% LiCl, and brine. Theorganics were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified by silica column chromatography(50% to 100% EtOAc/hexanes) to afford methyl{(2S)-1-[(2S,5S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(950 mg, 91%).

Methyl[(2S)-3-methyl-1-{(2S,5S)-2-methyl-5-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrolidin-1-yl}-1-oxobutan-2-yl]carbamate

To methyl{(2S)-1-[(2S,5S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(950 mg, 1.74 mmol) in dioxane (17 mL) was added bis(pinacolato)diboron(662 mg, 2.61 mmol), KOAc (512 mg, 5.22 mmol), X-Phos (25 mg, 0.05mmol), and Pd₂dba₃ (80 mg, 0.08 mmol). The solution was degassed with N₂for 10 min, then heated to 90° C. for 16 h. The solution was cooled tort, diluted with EtOAc, washed with saturated aqueous NaHCO₃, brine,dried with Na₂SO₄, and concentrated. Purification by silica gelchromatography (30% to 75% gradient using 5% MeOH/EtOAc to Hexanes) toafford methyl[(2S)-3-methyl-1-{(2S,5S)-2-methyl-5-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate(800 mg, 72%).

tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate

To a solution of[(2S)-3-methyl-1-{(2S,5S)-2-methyl-5-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-1-oxobutan-2-yl]carbamate(269 mg, 0.42 mmol), methyl(S)-1-((2S,4S)-2-(5-bromo-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(206 mg, 0.54 mmol), tetrakis(triphenylphosphine) palladium(0) (49 mg,0.042 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (31 mg,0.042 mmol) in DMSO (3 mL) and dioxanes (3 mL) was added a solution ofpotassium carbonate (2M in water, 0.69 mL, 1.39 mmol). The resultingmixture was degassed and then heated to 95° C. for 2 h. After cooling toroom temperature, the reaction was diluted with ethyl acetate. Theorganics were washed with saturated sodium bicarbonate and brine, driedover Na₂SO₄ and concentrated. The crude residue was purified by flashchromatography (1 to 20% MeOH/EtOAc) to yield tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(202 mg, 63%).

Methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

A solution of tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(80 mg, 0.11 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for3 h. The reaction was concentrated and the crude material dissolved inDMF (1.5 mL). To this solution was added a solution of(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (29 mg, 0.14 mmol) andCOMU (52 mg, 0.12 mmol). To the resulting solution was addeddiisopropylethylamine (0.057 mL, 0.33 mmol). After stirring for 2 h atroom temperature, the reaction was quenched with 1N HCl (0.200 mL) andpurified by HPLC. After lyophilization, the TFA salt was dissolved inEtOAc and washed with saturated NaHCO₃. The organic phase was dried overNa₂SO₄ and concentrated. The free base was then dissolved in MeCN/H₂Oand lyophilized to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate:(42 mg, 45%). LCMS-ESI⁺: calculated for C₄₈H₅₂N₈O₇: 852.4. observed[M+1]⁺: 854.2.

Example QG

Methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(60 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C.for 3 h and then concentrated under reduced pressure. The crude residuewas treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (21mg, 0.12 mmol), HATU (36 mg, 0.095 mmol) and DMF (1.5 mL), thenN-methylmorpholine (0.027 mL, 0.24 mmol) was added dropwise. After 3 h,the mixture was quenched with 1N HCl (0.100 mL) and then purified byHPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(33 mg, 51%).

LCMS-ESI⁺: calculated for C₄₅H₅₄N₈O₇: 818.4. observed [M+1]⁺: 820.2.

Example QH

Methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate(20 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C.for 3 h and then concentrated under reduced pressure. The crude residuewas treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid(8 mg, 0.04 mmol), HATU (12 mg, 0.03 mmol) and DMF (0.5 mL), thenN-methylmorpholine (0.009 mL, 0.078 mmol) was added dropwise. After 3 h,the mixture was quenched with 1N HCl (0.100 mL) and then purified byHPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(7.5 mg, 35%).

LCMS-ESI⁺: calculated for C₄₅H₅₄N₈O₈: 834.4. observed [M+1]⁺: 835.7.

Example QI

(2S,2′S,5S,5′S)-1-tert-butyl‘2,2-2,2’-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-oxoethane-2,1-diyl)bis(5-methylpyrrolidine-1,2-dicarboxylate)

A mixture of1,1′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-bromoethanone)(400 mg, 0.88 mmol)), and(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(507 mg, 2.21 mmol) in 10 mL DMF with triethylamine (0.385 mL, 2.21mmol) was heated at 80° C. for 4 hours. The solution was cooled to rtthen diluted with EtOAc and washed successively with 1N HCl, saturatedaqueous NaHCO₃, and brine. The organic phase was dried over Na₂SO₄,concentrated, and purified by silica gel chromatography (20% to 50%EtOAc/Hexanes) to afford (2S,2′S,5S,5′S)-1-tert-butyl‘2,2-2,2’-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-oxoethane-2,1-diyl)bis(5-methylpyrrolidine-1,2-dicarboxylate):(208 mg, 32%).

(2S,2′S,5S,5′S)-tert-butyl5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-1-carboxylate)

A mixture of (2S,2′S,5R,5′R)-1-tert-butyl (2S,2′S,5S,5′S)-1-tert-butyl‘2,2-2,2’-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-oxoethane-2,1-diyl)bis(5-methylpyrrolidine-1,2-dicarboxylate)(208 mg, 0.28 mmol), ammonium acetate (323 mg, 4.2 mmol), toluene (2.5mL) and 2-methoxypropanol (0.25 mL) was heated at reflux for 4 h. Thesolution was cooled to rt then diluted with EtOAc and washedsuccessively with saturated aqueous NaHCO₃ and brine. The organic phasewas dried over Na₂SO₄, concentrated, and purified by silica gelchromatography (20% to 50% EtOAc/Hexanes) to afford(2S,2′S,5S,5′S)-tert-butyl5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-1-carboxylate)(163 mg, 82%).

Dimethyl(2S,2′S)-1,1′-((2S,2′S,5S,5′S)-5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

(2S,2′S,5 S,5′S)-tert-butyl5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-1-carboxylate)(81 mg, 0.11 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for3 h and then concentrated under reduced pressure. The crude residue wastreated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (50 mg,0.12 mmol), HATU (88 mg, 0.23 mmol) and DMF (1 mL), thenN-methylmorpholine (0.060 mL, 0.55 mmol) was added dropwise. After 3 h,the mixture was quenched with 1N HCl (0.100 mL) and then purified byHPLC to afford dimethyl(2S,2′S)-1,1′-((2S,2′S,5S,5′S)-5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(62 mg, 68%).

LCMS-ESI⁺: calculated for C₄₅H₅₄N₈O₈: 822.4. observed [M+1]⁺: 823.2.

Example QJ

Dimethyl(2S,2′S,3R,3′R)-1,1′-((2S,2′S,5S,5′S)-5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate

Dimethyl(2S,2′S,3R,3′R)-1,1′-((2S,2′S,5S,5′S)-5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methoxy-1-oxobutane-2,1-diyl)dicarbamate:The title compound was prepared as described for Example QI,substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. LCMS-ESI⁺:calculated for C₄₄H₅₄N₈O₁₀: 854.4. observed [M+1]⁺: 856.0. ¹H NMR (CD₃CNwith D₂O) 7.600 (s, 2H), 7.303 (s, 1H), 7.189 (s, 1H), 7.093 (m, 4H),5.237 (s, 4H), 4.581 (m, 2H), 4.344 (m, 2H), 3.608 (s, 6H), 3.580 (m,2H), 3.294 (s, 2H), 3.243 (s, 6H), 2.460 (m, 2H), 2.3-2.1 (m, 4H),1.9-1.82 (m, 2H), 1.425 (d, 6H, J=6.4 Hz), 1.067 (d, 6H, J=6.0 Hz).

Example QK

(2S,4S)-tert-butyl2-(5-(7-(2-((2S,5S)-1-(benzyloxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

A mixture of1,1′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(2-bromoethanone)(1.08 g, 2.39 mmol)),(2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid(819 mg, 3.11 mmol), and(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid (806 mg, 3.11 mmol) in 24 mL DMF with triethylamine (1.25 mL, 7.18mmol) was heated at 80° C. overnight. The solution was cooled to rt thendiluted with EtOAc and washed successively with 1N HCl, saturatedaqueous NaHCO₃, and brine. The organic phase was dried over Na₂SO₄ thenconcentrated to afford the crude mixture (1.86 grams). To the crudemixture (1.86 grams) ammonium acetate (2.65 g, 34.3 mmol), toluene (20mL) and 2-methoxypropanol (2.5 mL) was heated at reflux overnight. Thesolution was cooled to rt then diluted with EtOAc and washedsuccessively with saturated aqueous NaHCO₃ and brine. The organic phasewas dried over Na₂SO₄, concentrated, and purified by silica gelchromatography (50% to 100% EtOAc/Hexanes) to afford (2S,4S)-tert-butyl2-(5-(7-(2-((2S,5S)-1-(benzyloxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(610 mg, 33%).

(2S,4S)-tert-butyl2-(5-(7-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

(2S,4S)-tert-butyl2-(5-(7-(2-((2S,5S)-1-(benzyloxycarbonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(300 mg, 0.38 mmol) 10 mL ethanol, and 19 mg 10% Pd/C was stirred underan atmosphere of hydrogen (balloon) overnight. Filtration through celiteand concentration afforded the crude amine. The crude amine wasdissolved in DMF (4 mL) and then(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (66 mg, 0.38 mmol),HATU (160 mg, 0.42 mmol) and N-methylmorpholine (0.084 mL, 0.76 mmol)were added. After 2 h, the reaction was diluted with EtOAc and washedsuccessively with saturated aqueous NaHCO₃, 5% LiCl, and brine. Theorganic phase was dried over Na₂SO₄, concentrated, and purified bysilica gel chromatography (1% to 20% MeOH/EtOAc) to afford(2S,4S)-tert-butyl2-(5-(7-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(177 mg, 58%).

Dimethyl(2S,2′S)-1,1′-((2S,2′S,5S,5′S)-5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate

A solution of (2S,4S)-tert-butyl2-(5-(7-(2-((2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate(177 mg, 0.11 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C.for 3 h. The reaction was concentrated to afford the crude HCl salt ofmethyl(S)-1-((2S,5S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(164 mg). A portion of the HCl salt of methyl(S)-1-((2S,5S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(124 mg) was dissolved in DMF (2 mL) and then(R)-2-(methoxycarbonylamino)-2-phenylacetic acid (38 mg, 0.18 mmol),COMU (64 mg, 0.15 mmol), diisopropylethylamine (0.078 mL, 0.45 mmol)were added. After stirring for 2 h at room temperature, the reaction wasquenched with 1N HCl (0.200 mL) and purified by HPLC. Afterlyophilization, the TFA salt was dissolved in EtOAc and washed withsaturated NaHCO₃. The organic phase was dried over Na₂SO₄ andconcentrated. The free base was then dissolved in MeCN/H₂O andlyophilized to afford dimethyl(2S,2′S)-1,1′-((2S,2′S,5S,5′S)-5,5′-(5,5′-(5,10-dihydrochromeno[5,4,3-cde]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methylpyrrolidine-5,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate(42 mg, 45%). LCMS-ESI⁺: calculated for C₄₄H₅₄N₈O₈: 886.4. observed[M+1]⁺: 888.1.

Example QL

methyl[(1R)-2-{(2S,4S)-2-[5-(7-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-4-methylpyrrolidin-1-yl}-2-oxo-1-phenylethyl]carbamate

Methyl[(1R)-2-{(2S,4S)-2-[5-(7-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-4-methylpyrrolidin-1-yl}-2-oxo-1-phenylethyl]carbamate:The title compound was prepared as described for Example QK,substituting(2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acidfor(2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylicacid. LCMS-ESI⁺: calculated for C₄₇H₅₂N₈O₈: 856.4. observed [M+1]⁺:858.3.

Example QM

Methyl{(2S)-1-[(2S,4S)-2-[5-(7-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

To the HCl salt of methyl(S)-1-((2S,5S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate(40 mg) in DMF (1 mL) was added(S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (13 mg, 0.075 mmol),HATU (21 mg, 0.055 mmol) and N-methylmorpholine (0.016 mL, 0.15 mmol).After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and thenpurified by HPLC to afford methyl{(2S)-1-[(2S,4S)-2-[5-(7-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate(43 mg). LCMS-ESI⁺: calculated for C₄₅H₅₆N₈O₉: 852.4. observed [M+1]⁺:853.1.

Compounds 290-539

Using procedures similar to those described herein, the followingcompounds of the invention were prepared.

LCMS (observed # Compound (M + H)⁺) 290

816.41 291

858.39 292

832.68 293

856.31 294

893.82 295

837.18 296

855.81 297

898.16 298

855.39 299

813.74 300

855.76 301

829.68 302

849.29 303

789.67 304

895.76 305

849.65 306

841.99 307

799. 2 308

785.61 309

897.6 310

846.18 311

830.27 312

842.39 313

811.4 314

847.27 315

823.33 316

823.58 317

879.39 318

819.76 319

795.63 320

861.72 321

835.74 322

869.71 323

880.29 324

853.27 325

847.8 326

873.2 327

915.18 328

889.76 329

803.61 330

803.71 331

785.7 332

823.69 333

781.73 334

869.76 335

843.79 336

817.78 337

835.72 338

855.75 339

813.78 340

801.75 341

803.66 342

777.68 343

859.8 344

859.8 345

889.78 346

823.9 347

819.71 348

811.67 349

827.76 350

869.82 351

861.75 352

808.8 353

891.91 354

856.3 355

881.96 356

891.68 357

875.8 358

902.8 359

775.29 360

850.56 361

785.64 362

815.68 363

845.74 364

872.1 365

882.02 366

881.85 367

843.8 368

835.8 369

881.03 370

794.21 371

823.25 372

801.63 373

873.22 374

835.67 375

839.73 376

819.2 377

847.2 378

844.1 379

835.8 380

857.99 381

837.2 382

925.0 383

811.0 384

864.76 385

882.2 386

824.18 387

815.88 388

824.18 389

830.18 390

805.76 391

819.85 392

861.79 393

785.68 394

822.28 395

840.26 396

914.1 (+Na) 397

831.76 398

831.81 399

897.45 400

791.7 401

858.18 402

858.12 403

845.63 404

854.48 405

825.78 406

893.76 407

764.8 408

792.41 409

830.93 410

823.75 411

855.68 412

825.72 413

825.67 414

819.79 415

841.65 416

812.66 417

807.59 418

845.8 419

831.8 420

899.99 421

931.17 422

791.6 423

825.61 424

823.68 425

851.14 426

825.67 427

793.69 428

827.2 429

847.8 430

847.8 431

890.1 432

825.28 433

841.66 434

827.64 435

827.71 436

875.7 437

909.79 438

863.77 439

897.78 440

851.23 441

808.29 442

841.76 443

883.8 444

887.1 445

916.1 446

842.16 447

861.1 448

973.0 (+Na) 449

911.9 450

859.1 451

891.8 452

891.7 453

865.2 454

865.8 455

857.2 456

852.44 457

824.22 458

811.24 459

835.6 460

824.2 461

891.8 462

917.2 463

903.1 464

1000.1 465

911.8 466

915.2 467

946.2 468

887.8 469

958.1 470

887.2 471

843.8 472

877.82 473

950.8 474

939.23 475

851.33 476

868.34 477

783.43 478

879.4 479

839.59 480

919.4 481

937.3 482

957.8 483

1061.9 484

1002.0 485

1145.8 486

891.8 487

948.2 488

919.8 489

939.9 490

972.1 491

959.7 492

959.1 493

838.2 494

837.3 495

835.7 496

887.69 497

920 498

835.34 499

823.35 500

817.34 501

853.1 502

887.8 503

837.35 504

823.2 505

891.3 506

827.37 507

865.32 508

875.71 509

880.03 510

511

889.68 512

876 513

884.13 514

867.8 515

833.35 516

836.04 517

841.47 518

803.2 519

839.48 520

839.9 521

853.1 522

876.1 523

878.0 524

822.2 525

866 526

806.11 527

839.91 528

902.05 529

892.07 530

892.15 531

902.21 532

902.13 533

866.3 534

866.11 535

867.58 536

838.29 537

890.14 538

870.11 539

882.09

BIOLOGICAL ASSAYS

Effect of Serum Proteins on Replicon Potency:

Replicon assays are conducted in normal cell culture medium (DMEM+10%FBS) supplemented with physiologic concentrations of human serum albumin(40 mg/mL) or α-acid glycoprotein (1 mg/mL). EC₅₀s in the presence ofhuman serum proteins are compared to the EC₅₀ in normal medium todetermine the fold shift in potency.

MT-4 Cell Cytotoxicity:

MT4 cells are treated with serial dilutions of compounds for a five dayperiod. Cell viability is measured at the end of the treatment periodusing the Promega CellTiter-Glo assay and non-linear regression isperformed to calculate CC₅₀.

Compound Concentration Associated with Cells at EC₅₀:

Huh-luc cultures are incubated with compound at concentrations equal toEC₅₀. At multiple time points (0-72 hours), cells are washed 2× withcold medium and extracted with 85% acetonitrile; a sample of the mediaat each time-point will also be extracted. Cell and media extracts areanalyzed by LC/MS/MS to determine the Molar concentration of compoundsin each fraction. Representative compounds of the invention have shownactivity.

Solubility and Stability:

Solubility is determined by taking an aliquot of 10 mM DMSO stocksolution and preparing the compound at a final concentration of 100 μMin the test media solutions (PBS, pH 7.4 and 0.1 N HCl, pH 1.5) with atotal DMSO concentration of 1%. The test media solutions are incubatedat room temperature with shaking for 1 hr. The solutions will then becentrifuged and the recovered supernatants are assayed on the HPLC/UV.Solubility will be calculated by comparing the amount of compounddetected in the defined test solution compared to the amount detected inDMSO at the same concentration. Stability of compounds after an 1 hourincubation with PBS at 37° C. will also be determined.

Stability in Cryopreserved Human, Dog, and Rat Hepatocytes:

Each compound is incubated for up to 1 hour in hepatocyte suspensions(100 μl, 80,000° Cells per well) at 37° C. Cryopreserved hepatocytes arereconstituted in the serum-free incubation medium. The suspension istransferred into 96-well plates (50 μL/well). The compounds are dilutedto 2 μM in incubation medium and then are added to hepatocytesuspensions to start the incubation. Samples are taken at 0, 10, 30 and60 minutes after the start of incubation and reaction will be quenchedwith a mixture consisting of 0.3% formic acid in 90% acetonitrile/10%water. The concentration of the compound in each sample is analyzedusing LC/MS/MS. The disappearance half-life of the compound inhepatocyte suspension is determined by fitting the concentration-timedata with a monophasic exponential equation. The data will also bescaled up to represent intrinsic hepatic clearance and/or total hepaticclearance.

Stability in Hepatic S9 Fraction from Human, Dog, and Rat:

Each compound is incubated for up to 1 hour in S9 suspension (500 μl, 3mg protein/mL) at 37° C. (n=3). The compounds are added to the S9suspension to start the incubation. Samples are taken at 0, 10, 30, and60 minutes after the start of incubation. The concentration of thecompound in each sample is analyzed using LC/MS/MS. The disappearancehalf-life of the compound in S9 suspension is determined by fitting theconcentration-time data with a monophasic exponential equation.

Caco-2 Permeability:

Compounds are assayed via a contract service (Absorption Systems, Exton,Pa.). Compounds are provided to the contractor in a blinded manner. Bothforward (A-to-B) and reverse (B-to-A) permeability will be measured.Caco-2 monolayers are grown to confluence on collagen-coated,microporous, polycarbonate membranes in 12-well Costar TRANSWELL®plates. The compounds are dosed on the apical side for forwardpermeability (A-to-B), and are dosed on the basolateral side for reversepermeability (B-to-A). The cells are incubated at 37° C. with 5% CO₂ ina humidified incubator. At the beginning of incubation and at 1 hr and 2hr after incubation, a 200-μL aliquot is taken from the receiver chamberand replaced with fresh assay buffer. The concentration of the compoundin each sample is determined with LC/MS/MS. The apparent permeability,Papp, is calculated.

Plasma Protein Binding:

Plasma protein binding is measured by equilibrium dialysis. Eachcompound is spiked into blank plasma at a final concentration of 2 μM.The spiked plasma and phosphate buffer is placed into opposite sides ofthe assembled dialysis cells, which will then be rotated slowly in a 37°C. water bath. At the end of the incubation, the concentration of thecompound in plasma and phosphate buffer is determined. The percentunbound is calculated using the following equation:

${\% \mspace{14mu} {Unbound}} = {100 \cdot \left( \frac{C_{f}}{C_{b} + C_{f}} \right)}$

Where C_(f) and C_(b) are free and bound concentrations determined asthe post-dialysis buffer and plasma concentrations, respectively.

CYP450 Profiling:

Each compound is incubated with each of 5 recombinant human CYP450enzymes, including CYP1A2, CYP2C9, CYP3A4, CYP2 D6 and CYP2C19 in thepresence and absence of NADPH. Serial samples will be taken from theincubation mixture at the beginning of the incubation and at 5, 15, 30,45 and 60 minutes after the start of the incubation. The concentrationof the compound in the incubation mixture is determined by LC/MS/MS. Thepercentage of the compound remaining after incubation at each time pointis calculated by comparing with the sampling at the start of incubation.

Stability in Rat, Dog, Monkey and Human Plasma:

Compounds will be incubated for up to 2 hours in plasma (rat, dog,monkey, or human) at 37° C. Compounds are added to the plasma at finalconcentrations of 1 and 10 μg/mL. Aliquots are taken at 0, 5, 15, 30,60, and 120 minutes after adding the compound. Concentration ofcompounds and major metabolites at each timepoint are measured byLC/MS/MS.

Evaluation of Cell-Based Anti-HCV Activity:

Antiviral potency (EC₅₀) was determined using a Renilla luciferase(RLuc)-based HCV replicon reporter assay. To perform the assay forgenotype 1 and 2a JFH-1, HCV 1b RLuc cells (harboring a dicistronicgenotype 1b Con1 replicon that encodes a RLuc reporter), or HCV 1a RLuccells (harboring a dicistronic genotype 1a H77 replicon that encodes aRLuc reporter), or HCV 2a JFH-1 Rluc cells (harboring a dicistronicgenotype 2a JFH-1 replicon that encodes a RLuc reporter) were dispensedinto 384-well plates. To perform the assay for genotype 2a (with M31present) or 2b, HCV 2a Rluc or 2b Rluc cells (both with M31 present)harboring a dicistronic NS5A chimeric genotype 2a JFH-1 replicon thatencodes a RLuc reporter and either genotype 2a J6 strain NS5A gene orgenotype 2b MD2b-1 NS5A gene (based on Los Alamos HCV database isolates,both with M31 present) respectively, were dispensed into 384-wellplates. To perform the assay for genotype 3 and 4, HCV 3a RLuc or 4aRluc cells harboring a dicistronic NS5A chimeric genotype 1b Con1replicon that encodes a RLuc reporter and either a consensus genotype 3aNS5A gene or genotype 4a NS5A gene (based on Los Alamos HCV databaseisolates) respectively, were dispensed into 384-well plates. Compoundswere re-suspended in DMSO at a concentration of 10 mM and seriallydiluted in DMSO either manually or using an automated pipetinginstrument. Serially diluted compounds were mixed with cell culturemedia and added to the seeded cells. DMSO was used as a negative(solvent) control, and the protease inhibitor ITMN-191 was included at aconcentration >100×EC₅₀ as a positive control. 72 hours later, cellswere lysed and Renilla luciferase activity quantified as recommended bythe manufacturer (Promega-Madison, Wis.). Non-linear regression wasperformed to calculate EC₅₀ values.

To determine the antiviral potency (EC₅₀) against resistance mutants,resistance mutations, including M28T, Q30R, Q30H, L31M, and Y93C ingenotype 1a NS5A and Y93H in genotype 1b NS5A, were introducedindividually into either 1a Rluc or 1b Rluc replicons described above bysite directed mutagenesis. Replicon RNA of each resistant mutant wastransfected into Huh-7 cured-51 cells and antiviral potency wasdetermined on these transfected cells as described above.

TABLE 1 # 1b (nM) 1a 1a Q30R 2a JFH 2a J6 2b 3a 4a  1

0.008 C C A A C C  2

0.005 C C A A C C  3

0.011 C C C  4

0.11 C C C C  5

0.037 A B C C  6

0.051 B B A C  7

0.008 C C C C  8

0.006 C C A A B C  9

0.022 C C A B C C 10

0.406 B C C C 11

0.258 B C 12

0.008 C C A A C C 13

0.015 C C B C C C 14

0.010 C C C C 15

0.026 C C C C 16

0.011 C C B B C C 17

0.014 C C A C 18

0.018 C C B C 19

0.010 B B A C 20

0.021 C C C C 21

0.060 C C C C 22

0.005 C C A A C C 23

0.067 C C C C 24

0.013 C C A A C C 25

0.021 C C C C 25b

0.176 C C B C C 25c

0.031 C C C B C C C 25d

0.048 C C C C C C C 1b (nM); 1a, Q30R, 2a JFH, 2a J6, 2b-A ≧ 44 nM, B =1-43.99 nM, C = 0.001-0.999 nM; 3a, 4a-A ≧ 5 nM, B = 1-4.99 nM, C =0.001-0.99 nM

TABLE 2 # 1b (nM) 1a 1a Q30R 2a JFH 2a J6 2b 3a 4a 26

0.012 C C B B C C 27

0.011 C C C 28

0.023 B B C 29

0.014 C C C 30

0.008 C C C 31

0.014 C C C 32

0.020 C C A 33

0.009 C C C 34

0.018 C C C 35

0.008 C C C 36

0.010 C C C 37

0.004 C B C 38

0.003 C B A 39

0.009 C B B C 40

0.005 C C B C 41

0.005 C C C C 42

0.008 C C B C 43

0.009 C C B C 44

0.032 C C B C 45

0.014 C C B C 46

0.007 C C B C 47

0.037 C C B C 48

0.007 C B B C 49

0.014 C C C C 50

0.031 C C C C 51

0.012 B B B C 52

0.009 C B B C 53

0.010 C C A C C 54

0.014 C C A C C 55

0.015 C C A C C 56

0.010 C C C C 57

0.009 C C C C 58

0.017 C C B C 59

0.016 C C C C 60

0.020 B C C C 61

0.087 C C B C 62

0.034 C C C C 63

0.019 C B C B A C C 64

0.018 C C C C 65

0.015 C C A C C 66

0.022 C C A C C 67

0.044 C C B C 68

0.025 C C B C C 69

0.035 C C C C 70

0.008 C B B C 71

0.013 C C C C 72

0.006 C C C C 73

0.038 C C B C 74

0.006 C C C C 75

0.005 C C C C 76

0.010 C B B C 77

0.029 C C C C 78

0.013 C C C C 79

0.231 C C C C 80

0.072 C C A C C 81

0.006 C C C C 82

0.042 C C C 83

0.094 C C A B C 84

0.007 C C C C 85

0.016 C C B C 86

0.034 C C B C 87

0.163 C C C 88

0.019 C C C C 89

0.064 C C C C 90

0.044 C C B C 91

0.100 C C B C 92

0.047 C C C C 93

0.023 C C C C 94

0.007 C C C C 95

0.028 C C C B C C 96

0.006 C B B C 97

0.009 B B A C 98

0.010 C C A B C 99

0.021 C C B C 100 

0.004 C C C C 101 

0.011 C C C C 102 

0.009 C C C C 1b (nM); 1a, 1a Q30R, 2a JFH, 2a J6, 2b-A ≧ 44 nM, B =1-43.99 nM, C = 0.001-0.999 nM; 3a, 4a-A ≧ 5 nM, B = 1-4.99 nM, C =0.001=0.99 nM

TABLE 3 1b 1a 2a 2a # (nM) 1a Q30R JFH J6 2b 3a 4a 103

0.007 C C C 104

0.007 C C C 105

0.042 B B B 106

0.024 B B B 107

0.024 B B B 108

0.028 C B A 109

1.597 B A A 110

0.009 C C C 111

0.160 B A A 112

0.018 C B A 113

0.014 C C C 114

0.011 C B A A B C 115

0.019 C C C 116

0.008 C C C C 117

0.007 C C C 118

0.027 C C C 119

0.020 C C C 120

0.014 C C C 121

0.011 C C B 122

0.009 C C A A C C 123

0.014 C C A A C C 124

0.011 C C C 125

0.032 C C C 126

127

0.006 C C C 128

0.005 C C A A C C 129

0.007 C C A A C C 130

0.006 C C C 131

0.009 C C C 132

0.003 C C C 133

134

0.007 C C C 135

0.006 C C A 136

0.005 C C C C 137

0.012 C C C 138

0.006 C C C 139

0.004 C B C 140

0.004 C B C 141

0.181 B B A 142

0.013 C C C 143

0.025 C B A 144

0.013 C C C 145

0.010 C C B 146

0.048 B B A 147

0.012 C C C 148

0.020 C C B 149

0.005 C C C 150

0.006 C C C 151

0.038 B B B 152

0.751 A A B 153

0.012 C C C 154

0.014 C C C 155

0.013 C B C 156

0.028 C C C 157

0.008 C C A B B C 158

0.010 C C C 159

0.006 C C A B C C 160

0.017 C C C 161

0.019 C C C 162

0.010 B B B 163

0.031 B B A 164

0.010 C C C 165

0.009 C C C 166

0.018 B C C 167

0.048 C C C 168

0.010 B B C 169

0.006 C C A A C C 170

0.032 C C C 171

0.026 C C C 172

0.011 C C C 173

0.024 C C C 174

0.015 C C C 175

0.011 C C C 176

0.006 C C C 177

0.010 C C C C 178

0.024 C C C 179

0.041 B B A 180

0.007 C C C 181

0.010 C C C C 182

0.050 C C C 183

0.013 C C B 184

0.009 C C C 185

0.008 B C C 186

0.004 C C 187

0.007 C C C 188

0.012 C C C 189

0.006 C C C 190

C 191

0.253 B A A 192

0.004 C C C 193

0.005 C C C 194

0.010 B B B 195

0.023 C C B C 196

0.036 B B A C 197

0.010 B B C C 198

0.018 C C A A B C 199

0.010 B B B C 200

0.009 B B B C 201

0.018 C B A C 202

0.017 C B A C 203

0.124 A B A C 204

0.030 C C C C 205

0.016 C C B C 206

0.005 C C B A C C 207

0.017 C B A C 208

0.009 C C C C 209

0.014 C C C 210

0.008 C C C 211

0.009 C B B 212

0.018 C C C 213

0.030 C C C 214

0.060 C C C 215

0.023 C C C C 216

0.006 C C C C 217

0.009 C C C C 218

0.010 C C C C 219

0.008 C C B C 220

0.011 C C B C 221

0.017 C C C C 222

0.023 C C C C 223

0.022 B C B C 224

0.008 C C C C 225

0.009 C C C C 226

0.009 B B B C 227

0.025 B C C C 228

0.015 C C C C 229

0.018 C C B C 230

0.012 C B B B 231

0.019 C B B C 232

0.004 C C C C 233

0.005 C C C C 234

0.011 C C C C 235

0.004 C C B C 236

0.011 C C C C 237

0.023 C C C C 238

0.005 C C C C 239

0.078 C C C C 240

0.010 C C B C 241

0.011 C B B C 242

0.008 C C C C 243

4.587 A A A C 244

0.014 C C C C 245

0.017 C C C C 246

0.045 C C C C 247

0.758 B A A C 248

0.024 B B A C 249

0.014 B B A C 250

0.004 C C C C 251

0.010 C C C C 252

0.004 C C C C 253

0.005 C C C C 254

0.077 C C 255

0.015 C B 256

0.015 C C C C 257

0.013 C C C C 258

0.005 C C C C 259

0.014 C C C C 260

0.004 C C A A C C 261

0.011 C C C C 262

0.008 C C C C 263

0.006 C C C C 264

0.006 C B B C 265

0.042 B B B C 266

0.009 C B B C 267

0.045 B A A C 268

0.007 C C C C 269

0.076 A B A C 270

0.032 C C C C 271

0.008 C C C C 272

#### A A A B 273

0.042 C C C C 274

0.011 B B B C 275

2.145 B A A A 276

#### A A 277

1.058 B A A B 278

0.013 C C B C 279

0.031 B B C C 280

0.047 B B C C 281

0.063 C C C C 282

0.007 C C A A C C 283

0.007 C C C C 284

4.620 B B A C 285

0.006 C C C C 286

0.003 C C C C 287

0.006 C C C C 288

0.009 C C C C 289

0.010 C C C C 1b (nM); 1a, 1a Q30R, 2a JFH, 2a J6, 2b-A ≧ 44 nM, B =1-43.99 nM, C = 0.001-0.999 nM; 3a, 4a-A ≧ 5 nM, B = 1-4.99 nM, C =0.001-0.99 nM

TABLE 4 1b 1a 2a 2a # (nM) 1a Q30R JFH J6 2b 3a 4a 290

0.017 C C C C 291

0.103 C C C C 292

0.059 C C C C 293

0.042 C C C C 294

0.010 C C C C 295

0.050 B C C C 296

0.063 C C C C 297

0.357 C C C C 298

0.077 C C C B C C 299

0.017 B B A C 300

0.023 B C B C 301

0.019 B B B C 302

0.021 C C C C 303

0.008 C C C C 304

0.004 B C B C 305

0.017 C C C C 306

0.011 C C A C C 307

0.091 C C C C 308

0.008 C C C C 309

0.219 C C C C 310

0.041 C C C C 311

0.025 C C C C 312

0.011 B C C C 313

0.079 C C C C 314

0.026 C C C C C C 315

0.023 C C B C C 316

0.242 C C C C 317

0.023 C C C C C C C 318

0.005 C C B C 319

0.021 C C C C C 320

0.010 C C C C 321

0.006 C C C C 322

0.021 C C C C 323

0.043 C C C C C C 324

0.006 C C C C 325

0.018 C B C C B C C 326

0.005 C C B C 327

0.011 C C C C 328

0.008 C C B C 329

0.008 C C B C 330

0.006 C C C C 331

0.006 C C C C 332

1.255 B C B C 333

0.646 B C B C 334

0.009 C C C C 335

0.027 C C C C 336

0.013 C C B C 337

0.010 C C C C 338

0.127 C C C C 339

0.026 C B C C B C C 340

0.013 C C C C 341

0.006 C C C C 342

0.010 C C C C 343

0.012 C C C C 344

0.010 C C C C 345

0.066 C C C C C 346

0.019 C C B C C 347

0.055 C C C C 348

0.011 C C C C 349

0.005 C C C C 350

0.020 C C C C 351

0.008 C C C C 352

0.011 C C B B C C 353

0.493 C C C C 354

0.031 C C C C 355

0.095 C C B B C C 356

0.022 C C C C C C 357

0.044 C C C C C C 358

0.057 C C C C C C 359

0.011 C C C C 360

0.053 C C C C 361

0.013 C C C C 362

0.011 C C C C 363

0.025 C C B A B C 364

0.335 C C C C C C 365

0.110 C C C C C C 366

0.075 C C C C 367

0.049 C C C C 368

0.012 C C C C 369

0.047 C C C C 370

0.028 C C A C C 371

0.007 C C A C 372

0.008 C C C C 373

0.013 C C B B C C 374

0.019 C C C B C C 375

0.015 B C C C C C 376

0.020 C C C C 377

0.022 C C C C 378

0.036 C C C C 379

0.009 C C C A C C 380

0.006 C C A C 381

0.008 C C A C C 382

0.006 C A A C 383

0.008 C C C C 384

0.013 C B C B C C 385

0.007 C C B B C C 386

0.015 C C A A C C 387

0.009 C C A A C C 388

0.008 C C A A C C 389

0.015 C C B C C 390

0.003 C C A B C 391

0.009 C C A A C 392

0.022 C C A B C 393

0.012 C C A C C 394

0.008 C C B A C C 395

0.004 C C A A C C 396

0.019 C C A C C 397

0.017 C C C C C C C 398

0.023 C C C C C C C 399

0.017 C C C C C 400

0.017 C C A A C C 401

0.015 C C B C C 402

0.015 C C A C C 403

0.014 C C C C C C 404

0.008 C C A C C 405

0.009 C C B C C 406

0.017 C C C C C 407

0.048 C C A B C 408

0.022 C C A A C C 409

0.584 C C B B C C 410

0.018 C C B A C C 411

0.034 C C B B C C 412

0.018 C C B C C C 413

0.017 C C B B C C 414

0.022 C B C B B C C 415

0.034 C C C C C C 416

0.043 C C C B C C 417

0.024 C C B B C C 418

0.035 C B C C C C C 419

0.786 B C C C C C 420

4.662 B C B B C B 421

0.041 C C C C C C 422

0.017 C C C B C C C 423

0.020 C C C C C C C 424

0.028 C B C C C C C 425

0.034 C C C C C C C 426

0.033 C C C C C C C 427

0.049 C B C B C C C 428

0.011 C C C B C C 429

0.033 C C B B C C 430

0.036 C B C C C C C 431

0.436 C C C C C C 432

0.022 C C B B C C 433

0.020 C C C C C C C 434

0.055 C C C C C C C 435

0.058 C C C C C C C 436

0.051 C C C C C C C 437

0.048 C C C C C C C 438

0.003 C B C A A C C 439

0.004 C C B A C C 440

0.048 C C C B B C 441

0.030 C C B A C C 442

0.029 C C C C C C 443

0.167 C C C C C C 444

1.763 B C B B C B 445

0.336 B C B B C C 446

0.030 C C C C C C C 447

2.046 B C C C C C 448

0.459 C C B C C C 449

0.139 C C C C C C 450

0.427 C C C C C C 451

0.070 C C C C C C 452

0.047 C C C B C C 453

0.018 C C C C C C C 454

0.028 C C C C C C C 455

0.029 C C C C C C 456

0.040 C C C C C C 457

0.009 C C A A C C 458

0.085 C C A A B C 459

0.033 C C C A C C 460

0.018 C C B C C C 461

0.020 C C B C C C 462

8.764 B C B B C B 463

#### B B A A B A 464

#### A B B A B A 465

0.176 C C C C C C 466

0.042 C C B B C C 467

#### A A A A A A 468

0.113 C C C C C C 469

0.752 C C C C C C 470

0.148 C C C C C C 471

0.015 C C C B C C 472

0.010 C C C C C C C 473

0.015 C C B B C C 474

0.025 C C B B C C 475

0.019 C C C C C C C 476

0.099 C C C C C C 477

0.089 C C C C C C 478

0.048 C C B C C C 479

0.034 C C C C C C 480

0.684 C C B C C C 481

0.058 C C C C C C 482

0.034 C C C C C C 483

0.814 B C A C C C 484

0.953 A C A A C C 485

0.170 B C A A C C 486

0.030 C C B C C C 487

0.027 C C A B C C 488

0.030 C C B C C C 489

0.048 C C C C C C 490

0.989 B C C C C C 491

0.066 C C C C C C 492

0.898 B C A B C C 493

0.030 C C A C C C 494

0.021 C C C C C C 495

0.026 C C C C C C C 496

0.011 C C C C C C 497

0.008 C C C C C C 498

0.016 C C C C C C C 499

0.032 C C C C C C 500

0.028 C C C B C C C 501

0.021 C C A B C C 502

0.016 C C C C C C C 503

0.041 C C C C C C 504

0.020 C C B B C C 505

0.019 C C C C C C 506

0.036 C C C C C C C 507

1.503 B C A B C C 508

0.026 C C C C C C 509

0.028 C C C C C C 510

0.050 C C C C C C 511

0.019 C C C C C C 512

0.035 C C C C C C 513

0.068 C C B B C C 514

0.010 C C C C C C 515

0.047 C C C B C C 516

0.024 C C C C C C 517

0.025 C C C C C C 518

0.010 C C B C C C 519

0.010 C C C C C 520

0.033 C C C C C 521

0.028 C C C C C 522

0.023 C C A C C 523

0.037 C C B C C 524

0.020 C C A B C 525

0.038 C C C C C C C 526

0.018 C C C C C C C 527

0.022 C C C C C C C 528

0.010 C C C C C 529

0.013 C C C C C 530

0.011 C C C C C 531

0.018 C C C C C 532

0.009 C C C C C 533

0.012 C C C C C 534

0.011 C C C C C 535

0.022 C C C C C 536

0.013 C C C C C C C 537

0.014 C C C C C 538

0.016 C C C C C C C 539

0.016 C C C C C C C 1b (nM); 1a, 1a Q30R, 2a JFH, 2a J6, 2b - A ≧ 44 nM,B = 1-43.99 nM, C = 0.001-0.999 nM; 3a, 4a - A ≧ 5 nM, B = 1-4.99 nM, C= 0.001-0.99 nM

TABLE 5 1b 1a 2a 2a # (nM) 1a Q30R JFH J6 2b 3a 4a 540

0.018 C C C C C C C 541

0.034 C C C C C 542

0.050 C C C C C 543

0.015 C C C C C C C 544

0.026 C C C C C C C 545

0.075 C C C C C C C 546

0.048 C C C C C C C 547

0.005 C C C C C C 548

0.006 C C C C C C C 549

0.007 C C C C C C 550

0.013 C C C C C C C 551

0.018 C C C C C C C 552

0.033 C C C C C C C 553

0.014 C C C C C C 554

0.012 C C C C C C C 555

0.021 C C C C C C C 556

0.008 C C A A C 557

0.028 C C C C C 558

0.014 C C C C C C 559

0.080 C C C C C C C 560

0.092 C C C C C C C 561

0.010 C C C C C C C 562

0.019 C C C C C C C 563

0.007 C C A A B C 564

0.012 C C B C C C 565

0.017 C C C C C C C 566

0.009 C C C C C C C 567

0.007 C C C C C C C 568

0.021 C C C C C C C 569

0.024 C C C C C C C 570

0.033 C C C C C C 571

0.114 C C C C C C C 572

0.044 C C C C C C C 573

0.030 C C C C C C C 574

0.016 C C C C C C C 575

0.029 C C C C C C C 576

0.014 C C B C C C 577

0.017 C C A B C C 578

0.022 C C A A C C 579

0.034 C C C C C C C 580

0.017 C C C C C C 581

0.007 C C C C C C C 582

0.010 C C C C C C C 583

0.018 C C C C C C 584

0.015 C C C C C C C 585

0.009 C C C C C C C 586

0.011 C C C C C C 587

0.041 C C C C C C C 588

0.017 C C C C C C C 589

0.011 C C C C C C C 590

0.014 C C C C C C C 591

0.016 C C C C C C 592

0.015 C C C C C C C 593

0.014 C B C C B C 594

0.013 C C C C C C 595

0.020 C C A B C C 596

0.013 C C C C C C C 597

0.005 C C C C C C 598

0.022 C C C C C 599

0.009 C C C C C C 600

0.007 C C C C C 601

0.014 C C C C C C 602

0.025 C C C C 603

0.015 C C C C C C 604

0.020 C C C C 605

0.015 C C C C C C 606

0.034 C C C C C C 607

0.067 C C C C 608

0.017 C C C C C 609

0.005 C C C C C C 610

0.013 C C C C C C 611

0.013 C C C C C C 612

0.005 C C C C C C 613

0.005 C C C C C C 614

0.013 C C C C C C 615

0.019 C C C C C C 616

0.018 C C C C C C 617

0.005 C C C C C C 618

0.020 C C C C C C 619

0.007 C C C C 620

0.081 C C C C 621

0.013 C C C C 622

0.016 C C C C C C 623

0.006 C C C C 624

625

0.031 C C C C C C 626

0.030 C C C C C C 627

0.039 C C C C C C 628

0.009 C C C C 629

630

631

0.006 C C C C A 632

0.008 C C C C 633

0.020 C C C C C C 634

0.015 C C C C 635

0.041 C C C C 636

0.011 C C C C C C 637

0.009 C C C C C C 638

0.009 C C C C 639

0.011 C C C C C C 640

0.015 C C C C 641

0.030 C C C C 642

0.014 C C C C 643

0.015 C C C C 644

645

646

647

648

1b (nM); 1a, 1a Q30R, 2a JFH, 2a J6, 2b − A ≧ 44 nM, B = 1-43.99 nM, C =0.001-0.999 nM; 3a, 4a − A ≧ 5 nM, B = 1-4.99 nM, C = 0.001-0.99 nM

1.-324. (canceled)
 325. A compound of formula (I):E^(1a)-V^(1a)—C(═O)—P^(1a)—W^(1a)—P^(1b)—C(═O)—V^(1b)-E^(1b)  (I)wherein: W^(1a) is:

optionally substituted with one or more groups independently selectedfrom the group consisting of halo, alkyl, haloalkyl, and cyano; E^(1a)is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl) or—N(H)(cycloalkyloxycarbonyl); or E^(1a)-V^(1a) taken together areR^(9a); E^(1b) is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl) or—N(H)(cycloalkyloxycarbonyl); or E^(1b)-V^(1b) taken together areR^(9b); V^(1a) and V^(1b) are each independently selected from the groupconsisting of:

one of P^(1a) and P^(1b) is

and the other of P^(1a) and P^(1b) is selected from the group consistingof:

and R^(9a) and R^(9b) are each independently:

or a pharmaceutically acceptable salt thereof.
 326. The compound ofclaim 325, wherein at least one of E^(1a) and E^(1b) is—N(H)(alkoxycarbonyl).
 327. The compound of claim 325, wherein at leastone of E^(1a) and E^(1b) is —N(H)C(═O)OCH₃.
 328. The compound of claim325, wherein both of E^(1a) and E^(1b) are —N(H)C(═O)OCH₃.
 329. Thecompound of claim 325, wherein at least one of V^(1a) and V^(1b) isselected from the group consisting of:


330. The compound of claim 325, wherein at least one of V^(1a) andV^(1b) is:


331. The compound of claim 325, wherein at least one of V^(1a) andV^(1b) is selected from the group consisting of:


332. The compound of claim 325, wherein V^(1a) and V^(1b) are eachindependently selected from the group consisting of:


333. The compound of claim 325, wherein at least one of P^(1a) andP^(1b) is selected from the group consisting of:


334. The compound of claim 325, wherein P^(1a) and P^(1b) are eachindependently selected from the group consisting of:


335. A compound selected from the group consisting of:


336. A pharmaceutical composition comprising a compound of claim 325 ora pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 337. The pharmaceutical compositionof claim 336, further comprising at least one therapeutic agent. 338.The pharmaceutical composition of claim 337, wherein said therapeuticagent is a ribavirin analog, NS3 protease inhibitor, NS5b polymeraseinhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant,non-nucleoside inhibitor of HCV, or other drug for treating HCV. 339.The pharmaceutical composition of claim 336, further comprising anucleoside analogue.
 340. The pharmaceutical composition of claim 339,wherein said nucleoside analogue is selected from the group consistingof ribavirin, viramidine, levovirin, a L-nucleoside, and isatoribine.341. A method of treating hepatitis C virus in a human patient in needthereof, said method comprising administering to the patient apharmaceutical composition which comprises a therapeutically effectiveamount of a compound of claim 325 or a pharmaceutically acceptablesalt-thereof.